Aromatic sulfone hydroxamic acids and their use as protease inhibitors

ABSTRACT

This invention is directed to aromatic sulfone hydroxamic acids (including hydroxamates) and salts thereof that, inter alia, inhibit matrix metalloproteinase (also known as “matrix metalloprotease” or “MMP”) activity and/or aggrecanase activity. This invention also is directed to a prevention or treatment method that comprises administering such a compound or salt in an MMP-inhibiting and/or aggrecanase-inhibiting effective amount to an animal, particularly a mammal having (or disposed to having) a pathological condition associated with MMP and/or aggrecanase activity.

PRIORITY CLAIM TO RELATED PATENT APPLICATION

This patent claims priority as a divisional of U.S. patent applicationSer. No. 10/142,737 (filed May 10, 2002) now U.S. Pat. No. 6,689,794,which, in turn, claims priority to U.S. Provisional Patent ApplicationSer. No. 60/290,375 (filed May 11, 2001). The entire text of each of theabove-referenced applications is incorporated by reference into thispatent.

FIELD OF THE INVENTION

This invention is directed generally to proteinase (also known as“protease”) inhibitors, and, more particularly, to aromatic sulfonehydroxamic acids (including hydroxamates) that, inter alia, inhibitmatrix metalloproteinase (also known as “matrix metalloprotease” or“MMP”) activity and/or aggrecanase activity. This invention also isdirected to compositions of such inhibitors, intermediates for thesyntheses of such inhibitors, methods for making such inhibitors, andmethods for preventing or treating conditions associated with MMPactivity and/or aggrecanase activity, particularly pathologicalconditions.

BACKGROUND OF THE INVENTION

Under normal conditions, connective tissue turnover and/or repairprocesses are in equilibrium with connective tissue production.Degradation of connective tissue is carried out by the action ofproteinases released from resident tissue cells and/or invadinginflammatory or tumor cells.

Matrix metalloproteinases, a family of zinc-dependent proteinases, makeup a major class of enzymes involved in degrading connective tissue.Matrix metalloproteinases are divided into classes, with some membershaving several different names in common use. Examples are: MMP-1 (alsoknown as collagenase 1, fibroblast collagenase, or EC 3.4.24.3); MMP-2(also known as gelatinase A, 72 kDa gelatinase, basement membranecollagenase, or EC 3.4.24.24), MMP-3 (also known as stromelysin 1 or EC3.4.24.17), proteoglycanase, MMP-7 (also known as matrilysin), MMP-8(also known as collagenase II, neutrophil collagenase, or EC 3.4.24.34),MMP-9 (also known as gelatinase B, 92 kDa gelatinase, or EC 3.4.24.35),MMP-10 (also known as stromelysin 2 or EC 3.4.24.22), MMP-11 (also knownas stromelysin 3), MMP-12 (also known as metalloelastase, humanmacrophage elastase or HME), MMP-13 (also known as collagenase 111), andMMP-14 (also known as MT1-MMP or membrane MMP). See, generally,Woessner, J. F., “The Matrix Metalloprotease Family” in MatrixMetalloproteinases, pp. 1-14 (Edited by Parks, W. C. & Mecham, R. P.,Academic Press, San Diego, Calif. 1998).

Excessive breakdown of connective tissue by MMPs is a feature of manypathological conditions. Inhibition of MMPs therefore provides a controlmechanism for tissue decomposition to prevent and/or treat thesepathological conditions. Such pathological conditions generally include,for example, tissue destruction, fibrotic diseases, pathological matrixweakening, defective injury repair, cardiovascular diseases, pulmonarydiseases, kidney diseases, liver diseases, ophthalmologic diseases, anddiseases of the central nervous system. Specific examples of suchconditions include, for example, rheumatoid arthritis, osteoarthritis,septic arthritis, multiple sclerosis, a decubitis ulcer, cornealulceration, epidermal ulceration, gastric ulceration, tumor metastasis,tumor invasion, tumor angiogenesis, periodontal disease, livercirrhosis, fibrotic lung disease, emphysema, otosclerosis,atherosclerosis, proteinuria, coronary thrombosis, dilatedcardiomyopathy, congestive heart failure, aortic aneurysm, epidermolysisbullosa, bone disease, Alzheimer's disease, defective injury repair(e.g., weak repairs, adhesions such as post-surgical adhesions, andscarring), post-myocardial infarction, bone disease, and chronicobstructive pulmonary disease.

Matrix metalloproteinases also are involved in the biosynthesis of tumornecrosis factors (TNFs). Tumor necrosis factors are implicated in manypathological conditions. TNF-α, for example, is a cytokine that ispresently thought to be produced initially as a 28 kD cell-associatedmolecule. It is released as an active, 17 kD form that can mediate alarge number of deleterious effects in vitro and in vivo. TNF-α cancause and/or contribute to the effects of inflammation (e.g., rheumatoidarthritis), autoimmune disease, graft rejection, multiple sclerosis,fibrotic diseases, cancer, infectious diseases (e.g., malaria,mycobacterial infection, meningitis, etc.), fever, psoriasis,cardiovascular diseases (e.g., post-ischemic reperfusion injury andcongestive heart failure), pulmonary diseases, hemorrhage, coagulation,hyperoxic alveolar injury, radiation damage, and acute phase responseslike those seen with infections and sepsis and during shock (e.g.,septic shock and hemodynamic shock). Chronic release of active TNF-α cancause cachexia and anorexia. TNF-α also can be lethal.

Inhibiting TNF (and related compounds) production and action is animportant clinical disease treatment. Matrix metalloproteinaseinhibition is one mechanism that can be used. MMP (e.g., collagenase,stromelysin, and gelatinase) inhibitors, for example, have been reportedto inhibit TNF-α release. See, e.g., Gearing et al. Nature, 370, 555-557(1994). See also, McGeehan et al., Nature, 370, 558-561 (1994). MMPinhibitors also have been reported to inhibit TNF-α convertase, ametalloproteinase involved in forming active TNF-α. See, e.g., WIPOInt'l Pub. No. WO 94/24140. See also, WIPO Int'l Pub. No. WO 94/02466.See also, WIPO Int'l Pub. No. WO 97/20824.

Matrix metalloproteinases also are involved in other biochemicalprocesses in mammals. These include control of ovulation, post-partumuterine involution, possibly implantation, cleavage of APP (β-amyloidprecursor protein) to the ainyloid plaque, and inactivation of(α₁-protease inhibitor (α₁-PI). Inhibiting MMPs therefore may be amechanism that may be used to control of fertility. In addition,increasing and maintaining the levels of an endogenous or administeredserine protease inhibitor (e.g., α₁-PI) supports the treatment andprevention of pathological conditions such as emphysema, pulmonarydiseases, inflammatory diseases, and diseases of aging (e.g., loss ofskin or organ stretch and resiliency).

Numerous metalloproteinase inhibitors are known. See, generally, Brown,P. D., “Synthetic Inhibitors of Matrix Metalloproteinases,” in MatrixMetalloproteinases, pp. 243-61 (Edited by Parks, W. C. & Mecham, R. P.,Academic Press, San Diego, Calif. 1998).

Metalloproteinase inhibitors include, for example, natural biochemicals,such as tissue inhibitor of metalloproteinase (TIMP), α2-macroglobulin,and their analogs and derivatives. These are high-molecular-weightprotein molecules that form inactive complexes with metalloproteinases.

A number of smaller peptide-like compounds also have been reported toinhibit metalloproteinases. Mercaptoamide peptidyl derivatives, forexample, have been reported to inhibit angiotensin converting enzyme(also known as ACE) in vitro and in vivo. ACE aids in the production ofangiotensin II, a potent pressor substance in mammals. Inhibiting ACEleads to lowering of blood pressure.

A wide variety of thiol compounds have been reported to inhibit MMPs.See, e.g., WO 95/13289. See also, W0 96/11209. See also, U.S. Pat. No.4,595,700. See also, U.S. Pat. No. 6,013,649.

A wide variety of hydroxamic acid compounds also have been reported toinhibit MMPs. Such compounds reportedly include hydroxamic acids havinga carbon backbone. See, e.g., WIPO Int'l Pub. No. WO 95/29892. See also,WIPO Int'l Pub. No. WO 97/24117. See also, WIPO Int'l Pub. No. WO97/49679. See also, European Patent No. EP 0 780 386. Such compoundsalso reportedly include hydroxamic acids having peptidyl backbones orpeptidomimetic backbones. See, e.g, WIPO Int'l Pub. No. WO 90/05719. Seealso, WIPO Int'l Pub. No. WO 93/20047. See also, WIPO Int'l Pub. No. WO95/09841. See also, WIPO Int'l Pub. No. WO 96/06074. See also, Schwartzet al., Progr. Med. Chem., 29:271-334(1992). See also, Rasmussen et al.,PharmacoL Ther., 75(1): 69-75 (1997). See also, Denis et al., Invest NewDrugs, 15: 175-185 (1997). Various piperazinylsulfonylmethyl hydroxamicacids and piperidinylsulfonylmethyl hydroxamic acids have additionallybeen reported to inhibit MMPs. See, WIPO Int'l Pub. No. WO 00/46221. Andvarious aromatic sulfone hydroxamic acids have been reported to inhibitMMPs. See, WIPO Int'l Pub. No. WO 99/25687. See also, WIPO Int'l Pub.No. WO 00/50396. See also, WIPO Int'l Pub. No. WO 00/69821.

It is often advantageous for an MMP inhibitor drug to target a certainMMP(s) over another MMP(s). For example, it is typically preferred toinhibit MMP-2, MMP-3, MMP-9, and/or MMP-13 (particularly MMP-13) whentreating and/or preventing cancer, inhibiting of metastasis, andinhibiting angiogenesis. It also is typically preferred to inhibitMMP-13 when preventing and/or treating osteoarthritis. See, e.g.,Mitchell et al., J Clin. Invest., 97(3):761-768 (1996). See also, Reboulet al., J Clin. Invest., 97(9):2011-2019 (1996). Normally, however, itis preferred to use a drug that has little or no inhibitory effect onMMP-1 and MMP-14. This preference stems from the fact that both MMP-1and MMP-14 are involved in several homeostatic processes, and inhibitionof MMP-1 and/or MMP-14 consequently tends to interfere with suchprocesses.

Many known MMP inhibitors exhibit the same or similar inhibitory effectsagainst each of the MMPs. For example, batimastat (a peptidomimetichydroxamic acid) has been reported to exhibit IC₅₀ values of from about1 to about 20 nM against each of MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9.Marimastat (another peptidomimetic hydroxamic acid) has been reported tobe another broad-spectrum MMP inhibitor with an enzyme inhibitoryspectrum similar to batimastat, except that Marimastat reportedlyexhibited an IC₅₀ value against MMP-3 of 230 nM. See Rasmussen et al.,Pharmacol. Ther., 75(1): 69-75 (1997).

Meta analysis of data from Phase I/II studies using Marimastat inpatients with advanced, rapidly progressive, treatment-refractory solidtumor cancers (colorectal, pancreatic, ovarian, and prostate) indicateda dose-related reduction in the rise of cancer-specific antigens used assurrogate markers for biological activity. Although Marimastat exhibitedsome measure of efficacy via these markers, toxic side effectsreportedly were observed. The most common drug-related toxicity ofMarimastat in those clinical trials was musculoskeletal pain andstiffness, often commencing in the small joints in the hands, and thenspreading to the arms and shoulder. A short dosing holiday of 1-3 weeksfollowed by dosage reduction reportedly permits treatment to continue.See Rasmussen et al., Pharmacol. Ther., 75(1): 69-75 (1997). It isthought that the lack of specificity of inhibitory effect among the MMPsmay be the cause of that effect.

Another enzyme implicated in pathological conditions associated withexcessive degradation of connective tissue is aggrecanase, particularlyaggrecanase-1 (also known as ADAMTS-4). Specifically, articularcartilage contains large amounts of the proteoglycan aggrecan.Proteoglycan aggrecan provides mechanical properties that help articularcartilage in withstanding compressive deformation during jointarticulation. The loss of aggrecan fragments and their release intosynovial fluid caused by proteolytic cleavages is a centralpathophysiological event in osteoarthritis and rheumatoid arthritis. Ithas been reported that two major cleavage sites exist in theproteolytically sensitive interglobular domains at the N-terminal regionof the aggrecan core protein. One of those sites has been reported to becleaved by several matrix metalloproteases. The other site, however, hasbeen reported to be cleaved by aggrecanase-1. Thus, inhibiting excessiveaggrecanase activity provides an additional and/or alternativeprevention or treatment method for inflammatory conditions. Seegenerally, Tang, B. L., “ADAMTS: A Novel Family of Extracellular MatrixProteases,” Int'l Journal of Biochemistry & Cell Biology, 33, pp. 33-44(2001). Such diseases reportedly include, for example, osteoarthritis,rheumatoid arthritis, joint injury, reactive arthritis, acutepyrophosphate arthritis, and psoriatic arthritis. See, e.g., EuropeanPatent Application Publ. No. EP 1 081 137 A1.

In addition to inflammatory conditions, there also is evidence thatinhibiting aggrecanase may be used for preventing or treating cancer.For example, excessive levels of aggrecanase-1 reportedly have beenobserved with a ghoma cell line. It also has been postulated that theenzymatic nature of aggrecanase and its similarities with the MMPs wouldsupport tumor invasion, metastasis, and angiogenesis. See Tang, Int'lJournal of Biochemistry & Cell Biology, 33, pp. 33-44 (2001).

Various hydroxamic acid compounds have been reported to inhibitaggrecanase-1. Such compounds include, for example, those described inEuropean Patent Application Publ. No. EP 1 081 137 A1. Such compoundsalso include, for example, those described in WIPO PCT Int'l Publ. No.WO 99/09000. Such compounds further include, for example, thosedescribed in WIPO PCT Int'l Publ. No. WO 00/59874.

In view of the importance of hydroxamic acid compounds in the preventionor treatment of several pathological conditions and the lack of enzymespecificity exhibited by two of the more potent MMP-inhibitor drugs thathave been in clinical trials, there continues to be a need forhydroxamic acids having greater enzyme specificity (preferably towardMAP-2, MMP-9, MMP-13, and/or aggrecanase (particularly toward MMP-13 insome instances, toward both MMP-2 and MMP-9 in other instances, andaggrecanase in yet other instances), while exhibiting little or noinhibition of MMP-1 and/or MMP-14. The following disclosure describeshydroxamic acid compounds that tend to exhibit such desirableactivities.

SUMMARY OF THE INVENTION

This invention is directed to hydroxamic acid compounds (and saltsthereof) that inhibit pathological protease activity (particularlycompounds that inhibit MMP-2, MMP-9, MMP-13, and/or aggrecanaseactivity), while generally exhibiting relatively little or no inhibitionagainst MMP-1 and MMP-14 activity. This invention also is directed to amethod for inhibiting MMP activity and/or aggrecanase activity,particularly pathological MMP and/or aggrecanase activity. Such a methodis particularly suitable to be used with mammals, such as humans, otherprimates (e.g., monkeys, chimpanzees. etc.), companion animals (e.g.,dogs, cats, horses, etc.), farm animals (e.g., goats, sheep, pigs,cattle, etc.), laboratory animals (e.g., mice, rats, etc.), and wild andzoo animals (e.g., wolves, bears, deer, etc.).

Briefly, therefore, the invention is directed in part to a compound orsalt thereof. The compound has a structure corresponding to Formula I:

Here:

-   -   A¹ is —H, alkylcarbonyl, alkoxycarbonyl, carbocyclylcarbonyl,        carbocyclylalkylcarbonyl, heterocyclylcarbonyl,        heterocyclylalkylcarbonyl, carbocyclyloxycarbonyl,        carbocyclylalkoxycarbonyl, aminoalkylcarbonyl,        alkyl(thiocarbonyl), alkoxy(thiocarbonyl),        carbocyclyl(thiocarbonyl), carbocyclylalkyl(thiocarbonyl),        heterocyclyl(thiocarbonyl), heterocyclylalkyl(thiocarbonyl),        carbocyclyloxy(thiocarbonyl), carbocyclylalkoxy(thiocarbonyl),        or aminoalkyl(thiocarbonyl). Except where A¹ is —H, any member        of this group optionally is substituted (i.e., it may be either        unsubstituted or substituted).    -   A² and A³, together with the carbon atom to which they are both        attached, form an optionally-substituted heterocyclyl containing        from 5 to 8 ring members.

In a preferred embodiment of the invention, X is -E¹-E²-E³-E⁴-E⁵. Inthis embodiment:

-   -   E¹ is —O—, —S(O)₂—, —S(O)—, —S—, —N(R¹)—, —C(O)—N(R¹)—,        —N(R¹)—C(O)—, or —C(R¹)(R²)—.    -   E² forms a link of at least 2 carbon atoms between E¹ and E³. E²        is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or        alkylcycloalkylalkyl. Any member of this group optionally is        substituted.    -   E³ is —C(O)—, —O—(CO)—, —C(O)—O—, —C(NR³)—, —N(R⁴)—,        —C(O)—N(R⁴)—, —N(R⁴)—C(O)—, —N(R⁴)—C(O)—N(R⁵)—, —S—, —S(O)—,        —N(R⁴)—S(O)₂—, —S(O)₂—N(R⁴)—, —C(O)—N(R⁴)—N(R⁵)—C(O)—,        —C(R⁴)(R⁶)—C(O)—, or —C(R⁷)(R⁸)—.    -   E⁴ is a bond, alkyl, or alkenyl. The alkyl and alkenyl        optionally are substituted.    -   E⁵ is —H, —OH, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl,        carbocyclyl, or heterocyclyl. Except where E⁵ is except —H or        —OH, any member of this group optionally is substituted. E⁵ is        not —H when both E³ is —C(R⁷)(R⁸)— and E⁴ is a bond.    -   R¹ and R² are independently selected from the group consisting        of —H and alkyl. The alkyl optionally is substituted. Neither R¹        nor R² forms a ring structure with E², E³, E⁴, or E⁵.    -   R³ is —H or —OH.    -   R⁴ and R⁵ are independently selected from the group consisting        of —H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and        heterocyclylalkyl. Except for —H, any member of this group        optionally is substituted. Neither R⁴ nor R⁵ forms a ring        structure with E², E⁴, or E⁵.    -   R⁶ is —CN or —OH.    -   R⁷ is —H, halogen, —OH, alkyl, alkoxy, or alkoxyalkyl. The        alkyl, alkoxy, and alkoxyalkyl optionally are substituted.    -   R⁸ is —OH or alkoxy. The alkoxy optionally is substituted.

In another preferred embodiment of the invention, X is -E¹-E²-E³-E⁴-E⁵.In this embodiment:

-   -   E¹ is —O—, —S(O)₂—, —S(O)—, —S—, —N(R¹)—, —C(O)—N(R¹)—,        —N(R¹)—C(O)—, or —C(R¹)(R²)—.    -   E² forms a link of at least 2 carbon atoms between E¹ and E3. E²        is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or        alkylcycloalkylalkyl. Any member of this group optionally is        substituted.    -   E³ is carbocyclyl or heterocyclyl. The carbocyclyl and        heterocyclyl have 5 or 6 ring members and optionally are        substituted.    -   E⁴ is a bond, alkyl, alkenyl, —O—, or —N(R³)—. The alkyl and        alkenyl optionally are substituted.    -   E⁵ is carbocyclyl or heterocyclyl. The carbocyclyl and        heterocyclyl optionally are substituted.    -   R¹ and R² are independently selected from the group consisting        of —H and alkyl. The alkyl optionally is substituted. Neither R¹        nor R² forms a ring structure with E², E³, E⁴, or E⁵.    -   R³ is —H or alkyl. The alkyl optionally is substituted.

In another preferred embodiment of the invention, X is-E¹-E²-C(E⁶)═C(E⁷)-E³-E⁴-E⁵. In this embodiment:

-   -   E¹ is —O—, —S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—,        or —C(R¹)(R²)—.    -   E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or        alkylcycloalkylalkyl. Any member of this group optionally is        substituted.    -   E⁴ is a bond or alkyl. The alkyl optionally is substituted.    -   E⁵ is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl,        or heterocyclyl. Any member of this group optionally is        substituted.    -   E⁶ is —H, halogen, or alkyl. The alkyl optionally is        substituted.    -   E⁷ is —H, alkyl, alkenyl, alkynyl, —S(O)₂—R³, —NO₂,        —C(O)—N(R³)(R⁴), —(C)(OR³), carbocyclyl, carbocyclylalkyl,        alkoxycarbocyclyl, —CN, —C═N—OH, or —C═NH. The alkyl, alkenyl,        alkynyl, carbocyclyl, carbocycylalkyl, and alkoxycarbocyclyl        optionally are substituted.

R¹ and R² are independently selected from the group consisting of —H andalkyl. The alkyl optionally is substituted. Neither R¹ nor R² forms aring structure with E², E⁴, E⁵, E⁶, or E⁷.

-   -   R³ and R⁴ are independently selected from the group consisting        of —H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl,        heterocyclylalkyl. Except where the member is —H, any member of        this group optionally is substituted.

In another preferred embodiment of the invention, X is -E¹-E²-E³-E⁴-E⁵.In this embodiment:

-   -   E¹ is —O—, —S(O)—, —S(O)—, —N(R³)—, —C(O)—N(R³)—, —(R³)—C(O)—,        or —C(R¹)(R²)—.    -   E² is a bond, alkyl, cycloalkyl, alkylcycloalkyl,        cycloalkylalkyl, or alkylcycloalkylalkyl. Except where the        member is a bond, any member of such group optionally is        substituted.    -   E³ is carbonylpyrrollidinyl. The carbonylpyrrollidinyl        optionally is substituted.    -   E⁴ is a bond, alkyl, or alkenyl. The alkyl and alkenyl        optionally and substituted.    -   E⁵ is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl,        or heterocyclyl. Any member of this group optionally is        substituted.    -   R¹ and R² are independently selected from the group consisting        of —H and alkyl. The alkyl optionally is substituted. Neither R¹        nor R² forms a ring structure with E², E³, E⁴, or E⁵.

In another preferred embodiment of the invention, X is -E¹-E²-E⁵. Inthis embodiment:

-   -   E¹ is —O—, —S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—,        or —C(R¹)(R²)—.    -   E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or        alkylcycloalkylalkyl. Any member of this group optionally is        substituted with one or more substituents independently selected        from the group consisting of halogen, alkyl, and haloalkyl.    -   E⁵ is alkyl, alkenyl, alkynyl, cycloalkyl, cyclopentenyl,        cyclopentadienyl, cyclohexenyl, or cyclohexadienyl. The        cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and        cyclohexadienyl optionally are substituted. The alkyl, alkenyl,        and alkynyl (a) contain at least 4 carbon atoms, and (b)        optionally are substituted with one or more substituents        selected from the group consisting of —OH, —NO₂, —CN, and        halogen.    -   R¹ and R² are independently selected from the group consisting        of —H and alkyl. The alkyl optionally is substituted. Neither R¹        nor R² forms a ring structure with E⁵.

In another preferred embodiment of the invention, X is -E¹-E²-E³-E⁴-E⁵.In this embodiment:

-   -   E¹ is —O—, —S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—,        or —C(R¹)(R²)—.    -   E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or        alkylcycloalkylalkyl. Any member of this group optionally is        substituted.    -   E³ is carbonylpiperidinyl. The carbonylpiperidinyl optionally is        substituted.    -   E⁴ is a bond, alkyl, or alkenyl. The alkyl and alkenyl        optionally are substituted.    -   E⁵ is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl,        or heterocyclyl. Any member of this group optionally is        substituted.    -   R¹ and R² are independently selected from the group consisting        of —H and alkyl. The alkyl optionally is substituted. Neither R¹        nor R² forms a ring structure with E², E³, E⁴, or E⁵.

In another preferred embodiment of the invention, X is -E¹-E²-E⁵. Inthis embodiment:

-   -   E¹ is —O—, —S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—,        or —C(R¹)(R²)—.    -   E² forms a link of at least 3 carbon atoms between E¹ and E⁵. E²        is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or        alkylcycloalkylalkyl. Any member of this group optionally is        substituted.    -   E⁵ is optionally-substituted heterocyclyl,        optionally-substituted fused-ring carbocyclyl, or substituted        single-ring carbocyclyl.    -   R¹ and R² are independently selected from the group consisting        of —H and alkyl. The alkyl optionally is substituted. Neither R¹        nor R² forms a ring structure with E⁵.

In another preferred embodiment of the invention, X is -E¹-E²-E⁵. Inthis embodiment:

-   -   E¹ is —O—, —S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—,        or —C(R¹)(R²)—.    -   E² forms a link of at least 4 carbon atoms between E¹ and E⁵. E²        is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or        alkylcycloalkylalkyl. Any member of this group optionally is        substituted.    -   E⁵ is —OH or optionally-substituted carbocyclyl.    -   R¹ and R² are independently selected from the group consisting        of —H and alkyl. The alkyl optionally is substituted. Neither R¹        nor R² forms a ring structure with E⁵.

In another preferred embodiment of the invention, X is -E¹-E²-O-E⁴-E⁵.In this embodiment:

-   -   E¹ is —S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—, or        —C(R¹)(R²)—.    -   E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or        alkylcycloalkylalkyl. Any member of this group optionally is        substituted.    -   E⁴ is a bond, alkyl, or alkenyl. The alkyl and alkenyl        optionally are substituted.    -   E⁵ is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl,        or heterocyclyl. Any member of this group optionally is        substituted.    -   R¹ and R² are independently selected from the group consisting        of —H and alkyl. The alkyl optionally is substituted. Neither R¹        nor R² forms a ring structure with E², E⁴, or E⁵.

In another preferred embodiment of the invention, X is —O-E²-O-E⁵. Inthis embodiment:

-   -   E² comprises at least 3 carbon atoms. E² is alkyl, cycloalkyl,        alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any        member of this group optionally is substituted.    -   E⁵ is —H, alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl,        carbocyclylalkoxyalkyl, heterocyclyl, heterocyclylalkyl, or        heterocyclylalkoxyalkyl. The alkyl, alkenyl, alkynyl, and        alkoxyalkyl optionally are substituted with one or more        substituents independently selected from the group consisting of        halogen, —OH, —NO₂, and —CN. the carbocyclyl,        carbocyclylalkoxyalkyl, heterocyclyl, heterocyclylalkyl, and        heterocyclylalkoxyalkyl optionally are substituted with one or        more substituents independently selected from the group        consisting of halogen, —OH, —NO₂, —CN, alkyl, haloalkyl, alkoxy,        haloalkoxy, alkoxyalkyl, halogen-substituted alkoxyalkyl,        —N(R³)(R⁴), —C(O)(R⁵), —S—R³, —S(O)₂—R³, carbocyclyl,        halocarbocyclyl, carbocyclylalkyl, and halogen-substituted        carbocyclylalkyl.    -   R¹ and R² are independently selected from the group consisting        of —H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and        heterocyclylalkyl. Except where the member is —H, any member of        this group optionally is substituted with one or more halogen.    -   R³ is —H, alkyl, —O—R⁴, —N(R⁴)(R⁵), carbocyclylalkyl, or        heterocyclylalkyl. The alkyl, carbocyclylalkyl, and        heterocyclylalkyl optionally are substituted with one or more        halogen.

R⁴ and R⁵ are independently selected from the group consisting of —H,alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, andheterocyclylalkyl. Except where the member is —H, any member of thisgroup optionally is substituted with one or more halogen.

In another preferred embodiment of the invention, X is —O-E²-O-E⁴-E⁵. Inthis embodiment:

-   -   E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or        alkylcycloalkylalkyl. Any member of this group optionally is        substituted. An atom in E² optionally is bound to an atom in E⁵        to form a ring.    -   E⁴ is a bond, alkyl, or alkenyl. The alkyl and alkenyl        optionally are substituted.    -   E⁵ is:        -   an optionally-substituted radical selected from the group            consisting of alkenyl, alkynyl, alkoxy, alkoxyalkyl,            fused-ring carbocyclyl, and heterocyclyl;        -   single-ring carbocyclyl substituted with one or more            substituents independently selected from the group            consisting of —OH, —NO₂, —CN, —N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵,            —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl, carbocyclylalkyl,            halogen-substituted carbocyclylalkyl, heterocyclyl,            haloheterocyclyl, heterocyclylalkyl, and halogen-substituted            heterocyclylalkyl; or        -   single-ring carbocyclyl having multiple substitutions.    -   R¹ and R² are independently selected from the group consisting        of —H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and        heterocyclylalkyl. Except where the member is —H, any member of        this group optionally is substituted with one or more halogen.    -   R³ is —H, alkyl, —O—R⁴, —N(R⁴)(R⁵), carbocyclylalkyl, or        heterocyclylalkyl. The alkyl, carbocyclylalkyl, and        heterocyclylalkyl optionally are substituted with one or more        halogen.    -   R⁴ and R⁵ are independently selected from the group consisting        of —H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and        heterocyclylalkyl. Except where the member is —H, any member of        this group optionally is substituted with one or more halogen.

In another preferred embodiment of the invention, X is-E¹-E²-S(O)₂-E⁴-E⁵. In this embodiment:

-   -   E¹ is —S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—, or        —C(R¹)(R²)—.    -   E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or        alkylcycloalkylalkyl. Any member of this group optionally is        substituted.    -   E⁴ is a bond, alkyl, or alkenyl. The alkyl and alkenyl        optionally are substituted.    -   E⁵ is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl,        or heterocyclyl. Any member of this group optionally is        substituted.    -   R¹ and R² are independently selected from the group consisting        of —H and alkyl. The alkyl optionally is substituted. Neither R¹        nor R² forms a ring structure with E², E⁴, or E⁵.

In another preferred embodiment of the invention, X is—O-E²-S(O)₂-E⁴-E⁵. In this embodiment:

-   -   E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or        alkylcycloalkylalkyl. Any member of this group optionally is        substituted.    -   E⁴ is alkyl or alkenyl. The alkyl and alkenyl optionally are        substituted.    -   E⁵ is —H, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, or        heterocyclyl. Any member of this group optionally is        substituted.

In another preferred embodiment of the invention, X is —O-E²-S(O)₂-E⁵.In this embodiment:

-   -   E² comprises less than 5 carbon atoms. E² is alkyl, cycloalkyl,        alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any        member of this group optionally is substituted.    -   E⁵ is alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl, or        heterocyclyl.    -    Any member of this group optionally is substituted.

In another preferred embodiment of the invention, X is —O-E²-S(O)₂-E⁵.In this embodiment:

-   -   E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or        alkylcycloalkylalkyl. Any member of this group optionally is        substituted.    -   E⁵ is alkyl, alkenyl, alkynyl, alkoxyalkyl, saturated        carbocyclyl, partially saturated carbocyclyl, or heterocyclyl.        Any member of this group optionally is substituted.

In another preferred embodiment of the invention, X is:

In this embodiment:

-   -   E¹—S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—, or        —C(R¹)(R²)—.    -   E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or        alkylcycloalkylalkyl. Any member of this group optionally is        substituted.    -   E⁴ is a bond, alkyl, or alkenyl, The alkyl and alkenyl        optionally are substituted.    -   E⁵ is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl,        or heterocyclyl. Any member of this group optionally is        substituted.    -   R¹ and R² are independently selected from the group consisting        of —H and alkyl. The alkyl optionally is substituted. Neither R¹        nor R² forms a ring structure with E², E⁴, or E⁵.

In another preferred embodiment of the invention, X is:

In this embodiment:

-   -   E² is a bond, alkyl, cycloalkyl, alkylcycloalkyl,        cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this        group optionally is substituted.    -   E⁴ is a bond, alkyl, or alkenyl. The alkyl and alkenyl        optionally are substituted.    -   E⁵ is substituted carbocyclyl or optionally-substituted        heterocyclyl. The carbocyclyl is substituted with:        -   two or more substituents independently selected from the            group consisting of halogen, —OH, —NO₂, —CN, alkyl,            haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl,            halogen-substituted alkoxyalkyl, —N(R¹)(R⁴), —C(O)(R⁵),            —S—R³, —S(O)₂—R³, carbocyclyl, halocarbocyclyl,            carbocyclylalkyl, and halogen-substituted carbocyclylalkyl;            or        -   a substituent selected from the group consisting of halogen,            —OH, —NO₂, —CN, —C(O)—O—R³, —S—R³, —S(O)₂—R³, carbocyclyl,            halocarbocyclyl, carbocyclylalkyl, and halogen-substituted            carbocyclylalkyl.    -    The heterocyclyl, on the other hand, optionally is substituted        with one or more substituents independently selected from the        group consisting of halogen, —OH, —NO₂, —CN, alkyl, haloalkyl,        alkoxy, haloalkoxy, alkoxyalkyl, halogen-substituted        alkoxyalkyl, —N(R³)(R⁴), —C(O)(R⁵), —S—R³, —S(O)₂—R³,        carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and        halogen-substituted carbocyclylalkyl.    -   R³ and R⁴ are independently selected from the group consisting        of —H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and        heterocyclylalkyl. Except where the member is —H, any member of        this group optionally is substituted with one or more halogen.    -   R⁵ is —H, alkyl, —O—R⁶, —N(R⁶)(R⁷), carbocyclylalkyl, or        heterocyclylalkyl.    -    The alkyl, carbocyclylalkyl, and heterocyclylalkyl optionally        are substituted with one or more halogen.    -   R⁶ and R⁷ are independently selected from the group consisting        of —H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and        heterocyclylalkyl. Except where the member is —H, any member of        this group optionally is substituted with one or more halogen.

In another preferred embodiment of the invention, X is -E¹-E²-E⁵. Inthis embodiment:

-   -   E¹ is —O—, —S(O)₂—, —S(O)—, —S—, —N(R¹)—, —C(O)—N(R¹)—,        —N(R¹)—C(O)—, or —C(R¹)(R²)—.    -   E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or        alkylcycloalkylalkyl. Any member of such group optionally is        substituted.    -   E⁵ is substituted heterocyclyl.    -   R¹ and R² are independently selected from the group consisting        of —H and alkyl. The alkyl optionally is substituted.    -   Neither R¹ nor R² forms a ring structure with E⁵.

In another preferred embodiment of the invention, X is -E¹-E²-E⁵. Inthis embodiment:

-   -   E¹ is —O—, —S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—,        or —C(R¹)(R²)—.    -   E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or        alkylcycloalkylalkyl. Any member of such group optionally is        substituted. In addition, E² comprises at least two carbon        atoms.    -   E⁵ is optionally-substituted heterocyclyl.    -   R¹ and R² are independently selected from the group consisting        of —H and alkyl. The alkyl optionally is substitute.    -   Neither R¹ nor R² forms a ring structure with E⁵.

In another preferred embodiment of the invention, X is -E¹-E²-E³-E⁴-E⁵.In this embodiment:

-   -   E¹ is —O—, —S(O)₂—, —S(O)—, —S—, —N(R¹)—, —C(O)—N(R¹)—,        —N(R¹)—C(O)—, or —C(R¹)(R²)—.    -   E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or        alkylcycloalkylalkyl. Any member of such group optionally is        substituted.    -   E³ is —C(O)—, —O—(CO)—, —C(O)—O—, —C(NR³)—, —N(R⁴)—,        —N(R⁴)—C(NR³)—, —C(NR³)—N(R⁴)—, —C(O)—N(R⁴)—, —N(R⁴)—C(O)—,        —N(R⁴)—C(O)—N(R⁵)—, —S—, —S(O)—, —N(R⁴)—S(O)₂—, —S(O)₂—N(R⁴)—,        —C(O)—N(R⁴)—N(R⁵)—C(O)—, —C(R⁴)(R⁶)—C(O)—, or —C(R⁷)(R⁸)—.    -   E⁴ is a bond, alkyl, or alkenyl. The alkyl and alkenyl        optionally are substituted.    -   E⁵ is carbocyclyl or heterocyclyl. The carbocyclyl and        heterocyclyl are:        -   substituted with a substituent selected from the group            consisting of optionally-substituted carbocyclyl,            optionally-substituted carbocyclylalkyl,            optionally-substituted heterocyclyl, and            optionally-substituted heterocyclylalkyl; and        -   optionally substituted with one or more substituents            independently selected from the group consisting of halogen,            —OH, —NO₂, —CN, alkyl, alkoxy, alkoxyalkyl, —N(R¹¹)(R¹²),            —C(O)(R¹³), —S—R¹¹, —S(O)₂—R¹¹, carbocyclyl,            carbocyclylalkyl, haloalkyl, haloalkoxy, halogen-substituted            alkoxyalkyl, halocarbocyclyl, halogen-substituted            carbocyclylalkyl, hydroxycarbocyclyl, and heteroaryl.    -   R¹ and R² are independently selected from the group consisting        of —H and alkyl, wherein the alkyl optionally is substituted.    -   R³ is —H or —OH.    -   R⁴ and R⁵ are independently selected from the group consisting        of —H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and        heterocyclylalkyl, wherein any member (except —H) of such group        optionally is substituted.    -   R⁶ is —CN or —OH.    -   R⁷ is —H, halogen, —OH, alkyl, alkoxy, or alkoxyalkyl. The        alkyl, alkoxy, and alkoxyalkyl optionally are substituted.    -   R⁸ is —OH or alkoxy. The alkoxy optionally is substituted.    -   R¹¹ and R¹² are independently selected from the group consisting        of —H, C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl,        heterocyclyl, and    -   heterocyclyl-C₁-C₈-alkyl. Any member (except —H) of such group        optionally is substituted with one or more halogen.    -   R¹³ is —H, C₁-C₈-alkyl, —O—R¹⁴, —N(R¹⁴)(R¹⁵),        carbocyclyl-C₁-C₈-alkyl, heterocyclyl-C₁-C₈-alkyl,        halo-C₁-C₈-alkyl, halogen-substituted carbocyclyl-C₁-C₈-alkyl,        or halogen-substituted heterocyclyl-C₁-C₈-alkyl.    -   R¹⁴ and R¹⁵ are independently selected from the group consisting        of —H, C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl,        heterocyclyl, and heterocyclyl-C₁-C₈-alkyl. Any member (except        —H) of such group optionally is substituted with one or more        halogen.    -   Neither R¹ nor R² forms a ring structure with E², E³, E⁴, or E⁵.    -   Neither R⁴ nor R⁵ forms a ring structure with E², E⁴, or E⁵.

This invention also is directed, in part, to a method for preventing ortreating a condition associated with pathological matrix metalloproteaseactivity in a mammal having the condition or predisposed to having thecondition. The method comprises administering an above-describedcompound or a pharmaceutically acceptable salt thereof to the mammal inan amount that is therapeutically-effective to prevent or treat thecondition.

This invention also is directed, in part, to a method for preventing ortreating a pathological condition in a mammal having the condition orpredisposed to having the condition. The method comprises administeringan above-described compound or a pharmaceutically acceptable saltthereof to the mammal in an amount that is therapeutically-effective toprevent or treat the condition. In this embodiment, the pathologicalcondition comprises tissue destruction, a fibrotic disease, pathologicalmatrix weakening, defective injury repair, a cardiovascular disease, apulmonary disease, a kidney disease, a liver disease, an ophthalmologicdisease, and a central nervous system disease.

This invention also is directed, in part, to a method for preventing ortreating a pathological condition in a mammal having the condition orpredisposed to having the condition. The method comprises administeringan above-described compound or a pharmaceutically acceptable saltthereof to the mammal in an amount that is therapeutically-effective toprevent or treat the condition. In this embodiment, the pathologicalcondition comprises osteoarthritis, rheumatoid arthritis, septicarthritis, tumor invasion, tumor metastasis, tumor angiogenesis, adecubitis ulcer, a gastric ulcer, a corneal ulcer, periodontal disease,liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis,multiple sclerosis, dilated cardiomyopathy, epidermal ulceration,epidermolysis bullosa, aortic aneurysm, defective injury repair, anadhesion, scarring, congestive heart failure, post myocardialinfarction, coronary thrombosis, emphysema, proteinuria, Alzheimer'sdisease, bone disease, and chronic obstructive pulmonary disease.

This invention also is directed, in part, to a method for preventing ortreating a condition associated with pathological TNF-α convertaseactivity in a mammal having the condition or predisposed to having thecondition. The method comprises administering an above-describedcompound or a pharmaceutically acceptable salt thereof to the mammal inan amount that is therapeutically-effective to prevent or treat thecondition.

This invention also is directed, in part, to a method for preventing ortreating a condition associated with pathological aggrecanase activityin a mammal having the condition or predisposed to having the condition.The method comprises administering an above-described compound or apharmaceutically acceptable salt thereof to the mammal in an amount thatis therapeutically-effective to prevent or treat the condition.

This invention also is directed, in part, to pharmaceutical compositionscomprising a therapeutically-effective amount of an above-describedcompound or a pharmaceutically-acceptable salt thereof.

This invention also is directed, in part, to a use of an above-describedcompound or a pharmaceutically acceptable salt thereof to prepare amedicament for treating a condition associated with pathological matrixmetalloprotease activity.

This invention also is directed, in part, to a use of an above-describedcompound or a pharmaceutically acceptable salt thereof to prepare amedicament for treating a condition associated with pathological TNF-αconvertase activity.

This invention also is directed, in part, to a use of an above-describedcompound or a pharmaceutically acceptable salt thereof to prepare amedicament for treating a condition associated with pathologicalaggrecanase activity.

Further benefits of Applicants' invention will be apparent to oneskilled in the art from reading this patent.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This detailed description of preferred embodiments is intended only toacquaint others skilled in the art with Applicants' invention, itsprinciples, and its practical application so that others skilled in theart may adapt and apply the invention in its numerous forms, as they maybe best suited to the requirements of a particular use. This detaileddescription and its specific examples, while indicating preferredembodiments of this invention, are intended for purposes of illustrationonly. This invention, therefore, is not limited to the preferredembodiments described in this patent, and may be variously modified.

A. Compounds of this Invention

In accordance with this invention, it has been found that certainaromatic sulfone hydroxamic acids tend to be effective for inhibitingMMPs, particularly those associated with excessive (or otherwisepathological) breakdown of connective tissue. Specifically, Applicantshave found that these hydroxamic acids tend to be effective forinhibiting proteases (particularly MMP-2, MMP-9, MMP-13, other MMP'sassociated with pathological conditions, and/or aggrecanase) that areoften particularly destructive to tissue if present or generated inabnormally excessive quantities or concentrations. Moreover, Applicantshave discovered that these hydroxamic acids tend to be selective towardinhibiting pathological protease activity, while avoiding excessiveinhibition of other proteases (particularly MMP-1 and/or MMP-14) thatare typically essential to normal bodily function (e.g., tissue turnoverand repair).

A-1. Preferred Compound Structures

As noted above, the compound of this invention generally has a structurecorresponding to Formula I:

A¹ is —H, alkylcarbonyl, alkoxycarbonyl, carbocyclylcarbonyl,carbocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclylalkylcarbonyl, carbocyclyloxycarbonyl,carbocyclylalkoxycarbonyl, amninoalkylcarbonyl, alkyl(thiocarbonyl),alkoxy(thiocarbonyl), carbocyclyl(thiocarbonyl),carbocyclylalkyl(thiocarbonyl), heterocyclyl(thiocarbonyl),heterocyclylalkyl(thiocarbonyl), carbocyclyloxy(thiocarbonyl),carbocyclylalkoxy(thiocarbonyl), or aminoalkyl(thiocarbonyl). Exceptwhere the member is —H, any member of this group optionally issubstituted.

In some preferred embodiments, A¹ is —H, C₁-C₈-alkylcarbonyl,C₁-C₈-alkoxycarbonyl, carbocyclylcarbonyl,carbocyclyl-C₁-C₈-alkylcarbonyl, heterocyclylcarbonyl,heterocyclyl-C₁-C₈-alkylcarbonyl, carbocyclyloxycarbonyl,carbocyclyl-C₁-C₈-alkoxycarbonyl, N(R^(A))(R^(B))-C₁-C₈-alkylcarbonyl,C₁-C₈-alkyl(thiocarbonyl), C₁-C₈-alkoxy(thiocarbonyl),carbocyclyl(thiocarbonyl), carbocyclyl-C₁-C₈-alkyl(thiocarbonyl),heterocyclyl(thiocarbonyl), heterocyclyl-C₁-C₈-alkyl(thiocarbonyl),carbocyclyloxy(thiocarbonyl), carbocyclyl-C₁-C₈-alkoxy(thiocarbonyl), orN(R^(A))(R^(B))-C₁-C₈-alkyl(thiocarbonyl). R^(A) and R^(B) areindependently selected from the group consisting of —H, C₁-C₈-alkyl,C₁-C₈-alkoxycarbonyl, C₁-C₈-alkylcarbonyl, carbocyclyl-C₁-C₈-alkyl, andcarbocyclyl-C₁-C₈-alkoxycarbonyl.

In generally more preferred embodiments, A¹ is —H.

A² and A³, together with the carbon atom to which they are bothattached, form an optionally-substituted heterocyclyl containing from 5to 8 ring members (i.e., from 5 to 8 atoms are bound together to formthe ring (or rings) of the heterocyclyl).

In some preferred embodiments, A² and A³, together with the carbon atomto which they both are attached, form an optionally-substitutedheterocyclyl containing either 5 or 6 ring members.

In some preferred embodiments, the compound corresponds in structure toone of the following formulas:

A⁴ is —H, alkyl, alkylcarbonyl, alkylcarbonylalkyl,alkylcarbonylalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,alkoxycarbonylalkylcarbonyl, alkylsulfonyl, alkyliminocarbonyl, alkenyl,alkynyl, alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl,alkylsulfoxidoalkyl, alkylthioalkenyl, alkylsulfoxidoalkenyl,alkylsulfonylalkenyl, carbocyclyl, carbocyclylalkyl,carbocyclylalkoxyalkyl, carbocyclylcarbonyl, carbocyclylsulfonyl,carbocyclyliminocarbonyl, carbocyclyloxycarbonyl, carbocyclylthioalkyl,carbocyclylsulfoxidoalkyl, carbocyclylsulfonylalkyl,carbocyclylthioalkenyl, carbocyclylsulfoxidoalkenyl,carbocyclylsulfonylalkenyl, heterocyclyl, beterocyclylalkyl,heterocyclylalkoxyalkyl, heterocyclylcarbonyl, heterocyclylthioalkyl,heterocyclylsulfoxidoalkyl, heterocyclylsulfonylalkyl,heterocyclylthioalkenyl, heterocyclylsulfoxidoalkenyl,heterocyclylsulfonylalkenyl, heterocyclylsulfonyl,heterocyclyliminocarbonyl, heterocyclylalkylcarbonyl,heterocyclylcarbonylalkylcarbonyl, heterocyclylsulfonyl,heterocyclylcarbonylalkyl, aminoalkylcarbonyl, aminocarbonyl,aminocarbonylalkylcarbonyl, aminosulfonyl, amninosulfonylalkyl,aminoalkyl, aminocarbonylalkyl, or aminoalkylsulfonyl. Except where themember is —H, any member of this group optionally is substituted.

In some preferred embodiments, A⁴ is —H, C₁-C₈-alkyl,C₁-C₈-alkylcarbonyl, C₁-C₈-alkylcarbonyl-C₁-C₈-alkyl,C₁-C₈-alkylcarbonyl-C₁-C₈-alkylcarbonyl, C₁-C₈-alkoxycarbonyl,C₁-C₈-alkoxycarbonyl-C₁-C₈-alkyl,C₁-C₈-alkoxycarbonyl-C₁-C₈-alkylcarbonyl, C₁-C₈-alkylsulfonyl,C₁-C₈-alkyliminocarbonyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl,C₁-C₈-alkoxy-C₁-C₈-alkyl, C₁-C₈-alkylthio-C₁-C₈-alkyl,C₁-C₈-alkylthio-C₂-C₈-alkenyl, C₁-C₈-alkylsulfoxido-C₁-C₈-alkyl,C₁-C₈-alkylsulfoxido-C₂-C₈-alkenyl, C₁-C₈-alkylsulfonyl-C₁-C₈-alkyl,C₁-C₈-alkylsulfonyl-C₂-C₈-alkenyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl,carbocyclyl-C₁-C₈-alkoxy-C₁-C₈-alkyl, carbocyclylcarbonyl,carbocyclylsulfonyl, carbocyclyliminocarbonyl, carbocyclyloxycarbonyl,carbocyclylthio-C₁-C₈-alkyl, carbocyclylthio-C₂-C₈-alkenyl,carbocyclylsulfoxido-C₁-C₈-alkyl, carbocyclylsulfoxido-C₂-C₈-alkenyl,carbocyclylsulfonyl-C₁-C₈-alkyl, carbocyclylsulfonyl-C₂-C₈-alkenyl,heterocyclyl, heterocyclyl-C₁-C₈-alkyl,heterocyclyl-C₁-C₈-alkoxy-C₁-C₈-alkyl, heterocyclylcarbonyl,heterocyclylthio-C₁-C₈-alkyl, heterocyclylsulfoxido-C₁-C₈-alkyl,heterocyclylsulfonyl-C₁-C₈-alkyl, heterocyclylthio-C₂-C₈-alkenyl,heterocyclylsulfoxido-C₂-C₈-alkenyl, heterocyclylsulfonyl-C₂-C₈-alkenyl,heterocyclylsulfonyl, heterocyclyliminocarbonyl,heterocyclyl-C₁-C₈-alkylcarbonyl,heterocyclylcarbonyl-C₁-C₈-alkylcarbonyl, heterocyclylsulfonyl,heterocyclylcarbonyl-C₁-C₈-alkyl, N(R^(C))(R^(D))-C₁-C₈-alkylcarbonyl,N(R^(C))(R^(D))-carbonyl, N(R^(C))(R^(D))-carbonyl-C₁-C₈-alkylcarbonyl,N(R^(C))(R^(D))-sulfonyl, N(R^(C))(R^(D))-sulfonyl-C₁-C₈-alkyl,N(R^(C))(R^(D))-C₁-C₈-alkyl, N(R^(C))(R^(D))-carbonyl-C₁-C₈-alkyl, orN(R^(C))(R^(D))-C₁-C₈-alkylsulfonyl. Any substitutable member of thisgroup optionally is substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH, —CN,—C(O)—OH, —SH, —SO₃H, and NO₂.

R^(C) and R^(D) are independently selected from the group consisting of—H, —OH, C₁-C₈-alkyl, C₁-C₈-alkyl-carbonyl, C₁-C₈-alkoxy-C₁-C₈-alkyl,C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₁-C₈-alkyl-thio-C₁-C₈-alkyl,C₁-C₈-alkyl-sulfoxido-C₁-C₈-alkyl, C₁-C₈-alkyl-sulfonyl-C₁-C₈-alkyl,carbocyclyl, carbocyclyl-C₁-C₈-alkyl, carbocyclylcarbonyl,carbocyclyl-C₁-C₈-alkoxy-C₁-C₈-alkyl, carbocyclylthio-C₁-C₈-alkyl,carbocyclylsulfoxido-C₁-C₈-alkyl, carbocyclylsulfonyl-C₁-C₈-alkyl,heterocyclyl, heterocyclyl-C₁-C₈-alkyl,heterocyclyl-C₁-C₈-alkoxy-C₁-C₈-alkyl, heterocyclylcarbonyl,heterocyclylthio-C₁-C₈-alkyl, heterocyclylsulfoxido-C₁-C₈-alkyl,heterocyclylsulfonyl-C₁-C₈-alkyl, aminocarbonyl-C₁-C₈-alkyl,C₁-C₈-alkyloxycarbonylamino-C₁-C₈-alkyl, and amino-C₁-C₈-alkyl. Exceptwhere the member is —H or OH, any member of this group optionally issubstituted with one or more substituents independently selected fromthe group consisting of halogen, —OH, —CN, —C(O)—OH, —SH, —SO₃H, andNO₂. The nitrogen of the amino-C₁-C₈-alkyl optionally is substitutedwith 1 or 2 substituents independently selected from the groupconsisting of C₁-C₈-alkyl, C₁-C₈-alkylcarbonyl, carbocyclyl, andcarbocyclyl-C₁-C₈-alkyl. No greater than one of R^(C) or R^(D) is —OH.

In some preferred embodiments, A⁴ is —H, C₁-C₆-alkyl (often preferablyC₁-C₄-alkyl, and more preferably ethyl), C₁-C₆-alkoxy-C₁-C₆-alkyl (oftenpreferably C₁-C₂-alkoxy-C₁-C₃-alkyl, and more preferably methoxyethyl),carbocyclyl (often preferably C₃-C₆-cycloalkyl or phenyl, and morepreferably cyclopropyl), carbocyclyl-C₁-C₆-alkyl (often preferablyC₃-C₆-cycloalkyl-C₁-C₃-alkyl or phenyl-C₁-C₃-alkyl, and more preferablycyclopropylmethyl or benzyl), C₁-C₆-alkylsulfonyl (often preferablyC₁-C₂-alkylsulfonyl, and more preferably methylsulfonyl), C₃-C₆-alkenyl(often preferably C₃-C₄-alkenyl, and more preferably C₃-alkenyl),C₃-C₆-alkynyl (often preferably C₃-C₄-alkynyl, and more preferablyC₃-alkynyl). Except where the member is —H, any member of these groupsoptionally is substituted with halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, A⁴ is —H, ethyl, methoxyethyl,cyclopropyl, cyclopropylmethyl, or benzyl.

X may be selected from a wide range of substituents. The followingdiscussion describes several specific preferred embodiments encompassingthe substituents that Applicants have found to be generally preferred.

Preferred Embodiment No. 1

In some embodiments of this invention, the compound has a structurecorresponding to Formula II:

A¹, A², and A³ are as defined above for Formula I.

E¹ is —O—, —S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—, or—C(R¹)(R²)—. E¹ alternatively may be —S—.

E² forms a link of at least 2 carbon atoms between E¹ and E³. E² isalkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, oralkylcycloalkylalkyl. Any member of this group optionally issubstituted.

In some preferred embodiments, E² is C₂-C₂₀-alkyl, cycloalkyl,C₁-C₁₀-alkylcycloalkyl, cycloalkyl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkylcycloalkyl-C₁-C₁₀-alkyl. Any member of this group optionallyis substituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, E² is C₂-C₆-alkyl optionally substitutedwith one or more halogen.

In some preferred embodiments, E² is C₂-C₆-alkyl.

In some preferred embodiments, E² is C₂—C₆-alkyl.

E³ is —C(O)—, —O—(CO)—, —C(O)—O—, —C(NR³)—, —N(R⁴)—, —C(O)—N(R⁴)—,—N(R⁴)—C(O)—, —N(R⁴)—C(O)—N(R⁵)—, —S—, —S(O)—, —N(R⁴)—S(O)₂—,—S(O)₂—N(R⁴)—, —C(O)—N(R⁴)—N(R⁵)—C(O)—, —C(R⁴)(R⁶)—C(O)—, or—C(R⁷)(R⁸)—.

E⁴ is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally aresubstituted.

In some preferred embodiments, E⁴ is a bond, C₁-C₂₀-alkyl, orC₂-C₂₀-alkenyl. The C₁-C₂₀-alkyl and C₂-C₂₀-alkenyl optionally aresubstituted with one or more substituents independently selected fromthe group consisting of halogen and carbocyclyl. This carbocyclyl, inturn, optionally is substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH, —NO₂,—CN, C₁-C₈-alkyl, C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl, carbocyclyl,carbocyclyl-C₁-C₈-alkyl, halo-C₁-C₈-alkyl, halo-C₁-C₈-alkoxy,halogen-substituted C₁-C₈-alkoxy-C₁-C₈-alkyl, halocarbocyclyl, andhalogen-substituted carbocyclyl-C₁-C₈-alkyl.

In some preferred embodiments, E⁴ a bond, C₁-C₃-alkyl, or C₂-C₃-alkenyl.The C₁-C₃-alkyl, and C₂-C₃-alkenyl optionally are substituted with oneor more substituents independently selected from the group consisting ofhalogen and carbocyclyl. This carbocyclyl, in turn, optionally issubstituted with one or more substituents independently selected fromthe group consisting of halogen, —OH, —NO₂, —CN, C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy,halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl, halocarbocyclyl, andhalogen-substituted carbocyclyl-C₁-C₆-alkyl.

In some preferred embodiments, E⁴ is a bond, C₁-C₃-alkyl, orC₂-C₃-alkenyl.

-   -   E⁵ is —H, —OH, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl,        carbocyclyl, or heterocyclyl. Except where E⁵ is —H or —OH, any        member of this group optionally is substituted. E⁵ is not —H        when both E³ is —C(R⁷)(R⁸)— and E⁴ is a bond.

In some preferred embodiments, E⁵ is —H, —OH, C₁-C₂₀-alkyl,C₂-C₂₀-alkenyl, C₂-C₂₀-alkynyl, C₁-C₂₀-alkoxy,C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl, carbocyclyl, or heterocyclyl. TheC₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, C₂-C₂₀-alkynyl, C₁-C₂₀-alkoxy, andC₁-C₂₀-alkoxy-C₁-C₂₀-alkyl optionally are substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO₂, and —CN. The carbocyclyl and heterocyclyl optionallyare substituted with one or more substituents independently selectedfrom the group consisting of halogen, —OH, —NO₂, —CN, C₁-C₈-alkyl,C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl, —N(R¹¹)(R¹²), —C(O)(R¹³),—S—R¹¹, —S(O)₂—R¹¹, carbocyclyl, carbocyclyl-C₁-C₈-alkyl,halo-C₁-C₈-alkyl, halo-C₁-C₈-alkoxy, halogen-substitutedC₁-C₈-alkoxy-C₁-C₈-alkyl, halocarbocyclyl, and halogen-substitutedcarbocyclyl-C₁-C₈-alkyl. The carbocyclyl and heterocyclyl alsooptionally are substituted with one or more substituents independentlyselected from the group consisting of C₁-C₈-alkylcarbocyclyl,halogen-substituted C₁-C₈-alkylcarbocyclyl, hydroxycarbocyclyl, andheterocyclyl.

In some preferred embodiments, E⁵ is —H, —OH, C₁-C₈-alkyl,C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl,carbocyclyl, or heterocyclyl. The C₁-C₈-alkyl, C₂-C₈-alkenyl,C₂-C₈-alkynyl, C₁-C₈-alkoxy, and C₁-C₈-alkoxy-C₁-C₈-alkyl optionally aresubstituted with one or more substituents independently selected fromthe group consisting of halogen, —OH, —NO₂, and —CN. The carbocyclyl andheterocyclyl optionally are substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH, —NO₂,—CN, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R¹¹)(R¹²),—C(O)(R¹³), —S—R¹¹, —S(O)₂—R¹¹, carbocyclyl, carbocyclyl-C₁-C₆-alkyl,halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, halogen-substitutedC₁-C₆-alkoxy-C₁-C₆-alkyl, halocarbocyclyl, halogen-substitutedcarbocyclyl-C₁-C₆-alkyl, C₁-C₆-alkylcarbocyclyl, halogen-substitutedC₁-C₆-alkylcarbocyclyl, hydroxycarbocyclyl, and heteroaryl.

In some preferred embodiments, E⁵ is furanyl, tetrahydropyranyl,dihydrofuranyl, tetrahydrofuranyl, thiophenyl, dihydrothiophenyl,tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl,imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl,oxathiolyl, oxazolyl, isoxazolyl, oxazolidinyl, isoxazolidinyl,thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl,isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl, oxatriazolyl,dioxazolyl, oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl,dihydropyranyl, pyridinyl, piperidinyl, diazinyl, piperazinyl,triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, morpholinyl,azepinyl, oxepinyl, thiepinyl, diazepinyl, indolizinyl, pyrindinyl,pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl,pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl,isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl,benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl,indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl,benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl,benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl,benzoxazinyl, benzisoxazinyl, tetrahydroisoquinolinyl, carbazolyl,xanthenyl, or acridinyl. Such substituent optionally is substituted withone or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, —CN, C₁-C₆-alkyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R¹¹)(R¹²), —C(O)(R¹³), —S—R¹¹, —S(O)₂—R¹¹,aryl, aryl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy,halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl, haloaryl, andhalogen-substituted aryl-C₁-C₆-alkyl. Any member of such group alsooptionally is substituted with one or more substituent independentselected from the group consisting of C₁-C₆-alkylaryl,halogen-substituted C₁-C₆-alkylaryl, hydroxyaryl, and heteroaryl.

In some preferred embodiments, E⁵ is indolizinyl, pyrindinyl,pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl,pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl,isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl,benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl,indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl,benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl,benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl,benzoxazinyl, benzisoxazinyl, tetrahydroisoquinolinyl, or pyridofuranyl.Such substituent optionally is substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH, —NO₂,—CN, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R¹¹)(R¹²),—C(O)(R¹³), —S—R¹¹, —S(O)₂—R¹¹, aryl, aryl-C₁-C₆-alkyl,halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, halogen-substitutedC₁-C₆-alkoxy-C₁-C₆-alkyl, haloaryl, halogen-substitutedaryl-C₁-C₆-alkyl. Such substituent also optionally is substituted withone or more substituents independently selected from the groupconsisting of C₁-C₆-alkylaryl, halogen-substituted C₁-C₆-alkylaryl,hydroxyaryl, and heteroaryl.

In some preferred embodiments, E⁵ is benzazinyl, benzofuranyl, ortetrahydroisoquinolinyl. Such substituent optionally is substituted withone or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, —CN, C₁-C₆-alkyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R¹¹)(R¹²), —C(O)(R¹³), —S—R¹¹, —S(O)₂—R¹¹,aryl, aryl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy,halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl, haloaryl, andhalogen-substituted aryl-C₁-C₆-alkyl. Such substituent also optionallyis substituted with one or more substituents independently selected fromthe group consisting of C₁-C₆-alkylaryl, halogen-substitutedC₁-C₆-alkylaryl, hydroxyaryl, and heteroaryl.

In some preferred embodiments, E⁵ is indolyl, benzoxazolyl,benzothienyl, benzothiazolyl, or pyridofuranyl. Such substituent anymember of such group optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO₂, —CN, C₁-C₆-alkyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R¹¹)(R¹²), —C(O)(R¹³), —S—R¹¹, —S(O)₂—R¹¹,aryl, aryl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy,halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl, haloaryl, andhalogen-substituted aryl-C₁-C₆-alkyl. Such substituent also optionallyis substituted with one or more substituents independently selected fromthe group consisting of C₁-C₆-alkylaryl, halogen-substitutedC₁-C₆-alkylaryl, hydroxyaryl, and heteroaryl.

R¹ and R² are independently selected from the group consisting of —H andalkyl. The alkyl optionally is substituted. Neither R¹ nor R² forms aring structure with E², E³, E⁴, or E⁵.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, and halo-C₁-C₈-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, and C₁-C₆-alkyl.

R³ is —H or —OH.

R⁴ and R⁵ are independently selected from the group consisting of —H,alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, andheterocyclylalkyl. Except for —H, any member of this group optionally issubstituted. Neither R⁴ nor R⁵ forms a ring structure with E², E⁴, orE⁵.

In some preferred embodiments, R⁴ and R⁵ are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₈-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, R⁴ and R⁵ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group optionally issubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R⁶ is —CN or —OH.

R⁷ is —H, halogen, —OH, alkyl, alkoxy, or alkoxyalkyl. The alkyl,alkoxy, and alkoxyalkyl optionally are substituted.

In some preferred embodiments, R⁷ is —H, halogen, —OH, C₁-C₈-alkyl,C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl, halo-C₁-C₈-alkyl,halo-C₁-C₈-alkoxy, or halogen-substituted C₁-C₈-alkoxy-C₁-C₈-alkyl.

In some preferred embodiments, R⁷ is —H, halogen, —OH, C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl,halo-C₁-C₆-alkoxy, or halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl.

In some preferred embodiments, R⁷ is —H, halogen, —OH, C₁-C₆-alkyl,C₁-C₆-alkoxy, or C₁-C₆-alkoxy-C₁-C₆-alkyl.

R⁸ is —OH or alkoxy. The alkoxy optionally is substituted.

In some preferred embodiments, R⁸ is —OH, C₁-C₈-alkoxy, orhalo-C₁-C₈-alkoxy.

In some preferred embodiments, R⁸ is —OH, C₁-C₆-alkoxy, orhalo-C₁-C₆-alkoxy.

In some preferred embodiments, R⁸ is —OH or C₁-C₆-alkoxy.

R¹¹ and R¹² are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R¹¹ and R¹² are independently selectedfrom the group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R¹³ is —H, C₁-C₈-alkyl, —O—R¹⁴, —N(R¹⁴)(R¹⁵), carbocyclyl-C₁-C₈-alkyl,heterocyclyl-C₁-C₈-alkyl, halo-C₁-C₈-alkyl, halogen-substitutedcarbocyclyl-C₁-C₈-alkyl, or halogen-substitutedheterocyclyl-C₁-C₈-alkyl.

In some preferred embodiments, R¹³ is —H, C₁-C₆-alkyl, —O—R¹⁴,—N(R¹⁴)(R¹⁵), carbocyclyl-C₁-C₆-alkyl, heterocyclyl-C₁-C₆-alkyl,halo-C₁-C₆-alkyl, halogen-substituted carbocyclyl-C₁-C₆-alkyl, orhalogen-substituted heterocyclyl-C₁-C₆-alkyl.

In some preferred embodiments, R¹³ is —H, C₁-C₆-alkyl, —O—R¹⁴,—N(R¹⁴)(R¹⁵), carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl.

R¹⁴ and R¹⁵ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but typically ispreferably not substituted with halogen.

In some preferred embodiments, R¹⁴ and R¹⁵ are independently selectedfrom the group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but typically is preferably notsubstituted with halogen.

Preferred Embodiment No. 1-a: E³ is —C(O)—

In some embodiments, E³ is —C(O)—.

In some such embodiments, E⁵ is optionally-substituted carbocyclyl, andoften preferably optionally-substituted cycloalkyl oroptionally-substituted aryl.

In some preferred embodiments, for example, E⁵ is optionally-substitutedphenyl. Such compounds include, for example:

Such compounds also include compounds wherein E⁵ is phenyl substitutedwith one or more substituents independently selected from the groupconsisting of aryl, haloaryl, aryl-C₁-C₆-alkyl, and halogen-substitutedaryl-C₁-C₆-alkyl. Here, the phenyl also optionally is substituted withone or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, —CN, C₁-C₆-alkyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R¹¹)(R¹²), —C(O)(R¹³), —S—R¹¹, —S(O)₂—R¹¹,aryl, aryl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy,halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl, haloaryl,halogen-substituted aryl-C₁-C₆-alkyl, C₁-C₆-alkylaryl,halogen-substituted C₁-C₆-alkylaryl, hydroxyaryl, and heteroaryl. Suchcompounds include, for example:

In other preferred embodiments, E⁵ is optionally-substitutednaphthalenyl. Such compounds include, for example:

In yet other preferred embodiments, E⁵ is optionally-substitutedC₅-C₆-cycloalkyl. Such compounds include, for example:

In some preferred embodiments, E⁵ is —H, —OH, C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy, or C₁-C₆-alkoxy-C₁-C₆-alkyl.The C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy, andC₁-C₆-alkoxy-C₁-C₆-alkyl optionally are substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO₂, and —CN. Such compounds include, for example:

Other such compounds include, for example:

In other preferred embodiments, E⁵ is optionally-substitutedheterocyclyl. In one such embodiment, E⁵ is optionally-substitutedthiophenyl. Such compounds include, for example:

Other compounds include, for example:

Preferred Embodiment No. 1-b: E³ is —S—

In some embodiments, E³ is —S—.

In some such embodiments, E⁵ is —H, —OH, C₁-C₈-alkyl, C₂-C₈-alkenyl,C₂-C₈-alkynyl, C₁-C₈-alkoxy, or C₁-C₈-alkoxy-C₁-C₈-alkyl. TheC₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₁-C₈-alkoxy, andC₁-C₈-alkoxy-C₁-C₈-alkyl optionally are substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO₂, and —CN. Such compounds include, for example:

In some preferred embodiments, E⁵ is optionally-substituted carbocyclyl,often preferably optionally-substituted aryl, and more preferablyoptionally-substituted phenyl. Such compounds include, for example:

In some preferred embodiments, E⁵ is optionally-substitutedheterocyclyl. In one such embodiment, E⁵ is optionally-substitutedpyrimidinyl. Such compounds include, for example:

In another such embodiment, E⁵ is optionally-substituted 2-fused-ringheterocyclyl. In some preferred embodiments, E⁵ isoptionally-substituted benzoxazolyl or optionally-substitutedbenzothiazolyl. Such compounds include, for example:

Other such compounds include, for example:

Preferred Embodiment No. 1-c: E³ is —N(R⁴)—C(O)—

In some other embodiments, E³ is —N(R⁴)—C(O)—.

In some such embodiments, E⁵ is optionally-substituted carbocyclyl. Insome preferred embodiments, E⁵ is optionally-substituted phenyl. Suchcompounds include, for example:

Other such compounds include, for example:

In some preferred embodiments, E⁵ is optionally-substitutednaphthalenyl. Such compounds include, for example:

In some preferred embodiments, E⁵ is optionally-substituted cycloalkyl.Such compounds include, for example, fused-ring cycloalkyls. Thesecompounds include, for example:

These compounds also include, for example:

In some preferred embodiments, E⁵ is optionally-substitutedC₅-C₆-cycloalkyl. These compounds include, for example:

In some preferred embodiments, E⁵ is optionally-substitutedheterocyclyl. In one such embodiment, E⁵ is an optionally-substitutedheterocyclyl selected from the group consisting of pyridinyl, pyrrolyl,isopyrrolyl, oxazolyl, isoxazole, thiazolyl, furanyl, and morpholinyl.In another such embodiment, E⁵ is an optionally-substituted heterocyclylselected from the group consisting of tetrazolyl, imidazolyl, andthienyl. Compounds of these embodiments include, for example:

Such compounds also include, for example:

In some preferred embodiments, E⁵ is optionally-substituted 2-fused-ringheterocyclyl. In some more preferred embodiments, E⁵ is anoptionally-substituted heterocyclyl selected from the group consistingof benzazinyl, benzofuranyl, tetrahydroisoquinolinyl or pyridofuranyl.In some other more preferred embodiments, E⁵ is anoptionally-substituted heterocyclyl selected from the group consistingof indolyl, benzoxazolyl, benzothienyl, and benzothiazolyl. Compounds ofsuch embodiments include, for example:

Other such compounds include, for example:

In some preferred embodiments, E⁵ is —OH, C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, C₁-C₆-alkoxy, or C₁-C₆-alkoxy-C₁-C₆-alkyl. Except wherethe member is —OH, any member of this group optionally is substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, and —CN. Such compounds include, forexample:

Preferred Embodiment No. 1-d: E³ is —C(O)—N(R⁴)—

In some embodiments, E³ is —C(O)—N(R⁴)—.

In some such embodiments, for example, E⁵ is optionally-substitutedcarbocyclyl, often preferably optionally-substituted aryl.

In some preferred embodiments, E⁵ is optionally-substituted phenyl. Suchcompounds include, for example:

Other such compounds include, for example:

In some preferred embodiments, E⁵ is optionally-substitutednaphthalenyl. These compounds include, for example:

In some preferred embodiments, E⁵ is —OH, C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, C₁-C₆-alkoxy, or C₁-C₆-alkoxy-C₁-C₆-alkyl. Except wherethe member is —OH, any member of this group optionally is substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, and —CN. Such compounds include, forexample:

Preferred Embodiment No. 1-e: E³ is —N(R⁴)—C(O)—N(R⁵)—

In some embodiments, E³ is —N(R⁴)—C(O)—N(R⁵)—. In some such embodiments,for example, E⁵ is optionally-substituted carbocyclyl, often preferablyoptionally-substituted aryl, and more preferably optionally-substitutedphenyl. Such compounds include, for example:

Preferred Embodiment No. 1-f: E³ is —S(O)₂—N(R⁴)—

In some embodiments, E³ is —S(O)₂—N(R⁴)—.

In some such embodiments, E⁵ is optionally-substituted carbocyclyl. Thecarbocyclyl may be, for example, cycloalkyl. Such compounds include, forexample:

In some preferred embodiments, the carbocyclyl is aryl (preferablyphenyl). Such compounds include, for example:

In some preferred embodiments, E⁵ is —H, —OH, C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy, or C₁-C₆-alkoxy-C₁-C₆-alkyl.Except where the member is —H or —OH, any member of this groupoptionally is substituted with one or more substituents independentlyselected from the group consisting of halogen, —OH, —NO₂, and —CN. Suchcompounds include, for example:

Preferred Embodiment No. 1-g: E³ is —N(R⁴)—S(O)₂—

In some embodiments, E³ is —N(R⁴)—S(O)₂—. In some such embodiments, E⁵is optionally-substituted carbocyclyl, often preferablyoptionally-substituted aryl, and more preferably optionally-substitutedphenyl. Such compounds include, for example:

Other such compounds include, for example:

Preferred Embodiment No. 1-h: E³ is —C(O)—N(R⁴)—N(R⁵)—C(O)—

In some embodiments, E³ is —C(O)—N(R⁴)—N(R¹⁵)—C(O)—. In some suchembodiments, E⁵ is optionally-substituted carbocyclyl, often preferablyoptionally-substituted aryl, and more preferably optionally-substitutedphenyl. Such compounds include, for example:

Preferred Embodiment No. 1-i: E³ is —C(R⁴)(R⁶)—C(O)—

In some embodiments, E³ is —C(R⁴)(R⁶)—C(O)—. In some such embodiments,E⁵ is optionally-substituted carbocyclyl, often preferablyoptionally-substituted aryl, and more preferably optionally-substitutedphenyl. Such compounds include, for example:

Preferred Embodiment No. 1-j: E³ is —O—C(O)—

In some embodiments, E³ is —O—C(O)—. In some such embodiments, E⁵ isoptionally-substituted heterocyclyl. In some preferred embodiments, E⁵is an optionally-substituted 2-fused-ring heterocyclyl. In someembodiments, for example, E⁵ is optionally-substitutedtetrahydroisoquinolinyl. Such compounds include, for example:

Preferred Embodiment No. 1-k: E³ is —N(R⁴)—

In some embodiments, E³ is —N(R⁴)—. In some such embodiments, E⁵ isoptionally-substituted heterocyclyl. In some preferred embodiments, E⁵is optionally-substituted 2-fused-ring heterocyclyl. In someembodiments, for example, E⁵ is optionally-substituted benzoxazolyl,benzothiazolyl, or benzimidazolyl. Such compounds include, for example:

Preferred Embodiment No. 1-l: E³ is —C(NR³)—

In some embodiments, E³ is —C(NR³)—. In some such embodiments, E⁵ isoptionally-substituted carbocyclyl, often preferablyoptionally-substituted aryl, and more preferably optionally-substitutedphenyl. Such compounds include, for example:

Preferred Embodiment No. 1-m: E³ is —C(R⁷)(R⁸)—

In some embodiments, E³ is —C(R⁷)(R⁸)—. In some such embodiments, E⁵ isoptionally-substituted carbocyclyl, often preferablyoptionally-substituted aryl, and more preferably optionally-substitutedphenyl. Such compounds include, for example:

Preferred Embodiment No. 1-n: E³ is —N(R⁴)—C(NR³)—

In some embodiments, E³ is —N(R⁴)—C(R³)—. In some such embodiments, E⁵is optionally-substituted carbocyclyl, often preferablyoptionally-substituted aryl, and more preferably optionally-substitutedphenyl. Such compounds include, for example:

Preferred Embodiment No. 2

In some embodiments of this invention, the compound has a structurecorresponding to Formula III:

A¹, A², and A³ are as defined above for Formula I.

E¹ is —O—, —S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—, or—C(R¹)(R²)—. E¹ alternatively may be —S—.

E² forms a link of at least 2 carbon atoms between E¹ and E³. E² isalkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, oralkylcycloalkylalkyl. Any member of this group optionally issubstituted.

In some preferred embodiments, E² is C₂-C₂₀-alkyl, cycloalkyl,C₁-C₁₀-alkylcycloalkyl, cycloalkyl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkylcycloalkyl-C₁-C₁₀-alkyl. Any member of this group optionallyis substituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, E² is C₂-C₆-alkyl optionally substitutedwith one or more halogen.

In some preferred embodiments, E² is C₂-C₅-alkyl optionally substitutedwith one or more halogen.

In some preferred embodiments, E² is C₂-C₅-alkyl.

In some preferred embodiments, E² is —(CH₂)_(m)—, wherein m is from 2 to5.

E³ is carbocyclyl or heterocyclyl. This carbocyclyl and heterocyclylhave 5 or 6 ring members and optionally are substituted.

In some preferred embodiments, E³ is carbocyclyl or heterocyclyl whereinthe carbocyclyl and heterocyclyl have 5 or 6 ring members and optionallyare substituted with one or more substituents independently selectedfrom the group consisting of halogen, —OH, keto, C₁-C₈-alkyl,C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl, carbocyclyl,carbocyclyl-C₁-C₈-alkyl, heterocyclyl, and heterocyclyl-C₁-C₈-alkyl.Except where the substituent is halogen, —OH, or keto, any of thesesubstituents optionally is substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH,C₁-C₈-alkyl, C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl, C₁-C₈-alkylthio,halo-C₁-C₈-alkyl, halo-C₁-C₈-alkoxy, halo-C₁-C₈-alkylthio, andhalogen-substituted C₁-C₈-alkoxy-C₁-C₈-alkyl.

In some preferred embodiments, E³ is carbocyclyl or heterocyclyl whereinthe carbocyclyl and heterocyclyl have 5 or 6 ring members and optionallyare substituted with one or more substituents independently selectedfrom the group consisting of halogen, —OH, keto, C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the substituent is halogen, —OH, or keto, any substituentof this group optionally is substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH,C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, halogen-substitutedC₁-C₆-alkoxy-C₁-C₆-alkyl, and halo-C₁-C₆-alkylthio.

E⁴ is a bond, alkyl, alkenyl, —O—, or —N(R³)—. The alkyl and alkenyloptionally are substituted.

In some preferred embodiments, E⁴ is a bond, —O—, —N(R³)—, C₁-C₂₀-alkyl,or C₂-C₂₀-alkenyl. The C₁-C₂₀-alkyl and C₂-C₂₀-alkenyl optionally aresubstituted with one or more substituents independently selected fromthe group consisting of halogen and carbocyclyl optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, —CN, C₁-C₈-alkyl, C₁-C₈-alkoxy,C₁-C₈-alkoxy-C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl,halo-C₁-C₈-alkyl, halo-C₁-C₈-alkoxy, halocarbocyclyl,halogen-substituted carbocyclyl-C₁-C₈-alkyl, and halogen-substitutedC₁-C₈-alkoxy-C₁-C₈-alkyl.

In some preferred embodiments, E⁴ is a bond, —O—, —N(R³)—, C₁-C₃-alkyl,or C₂-C₃-alkenyl. The C₁-C₃-alkyl and C₂-C₃-alkenyl optionally aresubstituted with one or more substituents independently selected fromthe group consisting of halogen and carbocyclyl optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, —CN, C₁-C₆-alkyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, carbocyclyl, carbocyclyl-C₁-C₆-alkyl,halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, halogen-substitutedC₁-C₆-alkoxy-C₁-C₆-alkyl, halocarbocyclyl, and halogen-substitutedcarbocyclyl-C₁-C₆-alkyl.

In some preferred embodiments, E⁴ is a bond, —O—, —N(R³)—, C₁-C₃-alkyl,or C₂-C₃-alkenyl.

In some preferred embodiments, E⁴ is a bond.

E⁵ is carbocyclyl or heterocyclyl. The carbocyclyl and heterocyclyloptionally are substituted. In some preferred embodiments, thecarbocyclyl and heterocyclyl optionally are substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO₂, —CN, keto, C₁-C₈-alkyl, C₁-C₈-alkoxy,C₁-C₈-alkoxy-C₁-C₈-alkyl, —N(R⁶)(R⁷), —C(O)(R⁸), —S—R⁶, —S(O)₂—R⁶,carbocyclyl, carbocyclyl-C₁-C₈-alkyl, halo-C₁-C₈-alkyl,halo-C₁-C₈-alkoxy, halogen-substituted C₁-C₈-alkoxy-C₁-C₈-alkyl,halocarbocyclyl, and halogen-substituted carbocyclyl-C₁-C₈-alkyl. Thecarbocyclyl and heterocyclyl also optionally are substituted with one ormore substituents independently selected from the group consisting ofC₂-C₈-alkenyl and C₂-C₈-alkynyl.

In some preferred embodiments, E⁵ is pyridinyl optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, —CN, C₁-C₆-alkyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R⁶)(R⁷), —C(O)(R⁸), —S—R⁶, —S(O)₂—R⁶,phenyl, phenyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy,halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl, halophenyl, andhalogen-substituted phenyl-C₁-C₆-alkyl. The pyridinyl also is optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₂-C₆-alkenyl and C₂-C₆-alkynyl.

In some preferred embodiments, E⁵ is piperidinyl, piperazinyl,imidazolyl, furanyl, thienyl, pyrimidyl, benzodioxolyl, benzodioxanyl,benzofuryl, or benzothienyl. Such substituent optionally is substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, —CN, C₁-C₆-alkyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R⁶)(R⁷), —C(O)(R⁸), —S—R⁶, —S(O)₂—R⁶,phenyl, phenyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy,halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl, halophenyl, andhalogen-substituted phenyl-C₁-C₆-alkyl. Such substituent also optionallyis substituted with one or more substituents independently selected fromthe group consisting of C₂-C₆-alkenyl and C₂-C₆-alkynyl.

In some preferred embodiments, E⁵ is phenyl optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, —CN, C₁-C₆-alkyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R⁶)(R⁷), —C(O)(R₈), —S—R⁶, —S(O)₂—R⁶,phenyl, phenyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy,halogen-substituted C₁-C₆-alkoxy-C₁-C-alkyl, halophenyl, andhalogen-substituted phenyl-C₁-C₆-alkyl. The phenyl also is optionallysubstituted with one or more substituents independently selected fromthe group consisting of C₂-C₆-alkenyl and C₂-C₆-alkynyl.

In some preferred embodiments, E⁵ is naphthalenyl optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, —CN, C₁-C₆-alkyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R⁶)(R⁷), —C(O)(R⁸), —S—R⁶, —S(O)₂—R⁶,phenyl, phenyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy,halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl, halophenyl, andhalogen-substituted phenyl-C₁-C₆-alkyl. The naphthalenyl also isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₂-C₆-alkenyl and C₂-C₆-alkynyl.

R¹ and R² are independently selected from the group consisting of —H andalkyl. The alkyl optionally is substituted. Neither R¹ nor R² forms aring structure with E², E³, E⁴, or E⁵.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, and halo-C₁-C₈-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl).

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H and C₁-C₆-alkyl.

R³ is —H or alkyl. The alkyl optionally is substituted.

In some preferred embodiments, R³ is —H, C₁-C₈-alkyl, orhalo-C₁-C₈-alkyl.

In some preferred embodiments, R³ is —H, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl.

In some preferred embodiments, R³ is —H or C₁-C₈-alkyl.

R⁶ and R⁷ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl,heterocyclyl-C₁-C₈-alkyl, halo-C₁-C₈-alkyl, halocarbocyclyl,halogen-substituted carbocyclyl-C₁-C₈-alkyl, haloheterocyclyl, andhalogen-substituted heterocyclyl-C₁-C₈-alkyl.

In some preferred embodiments, R⁶ and R⁷ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R⁸ is —H, C₁-C₈-alkyl, —O—R⁹, —N(R⁹)(R¹⁰), carbocyclyl-C₁-C₈-alkyl,heterocyclyl-C₁-C₈-alkyl, halo-C₁-C₈-alkyl, halogen-substitutedcarbocyclyl-C₁-C₈-alkyl, or halogen-substitutedheterocyclyl-C₁-C₈-alkyl.

In some preferred embodiments, R⁸ is —H, C₁-C₆-alkyl, —O—R⁹,—N(R⁹)(R¹⁰), carbocyclyl-C₁-C₆-alkyl, heterocyclyl-C₁-C₆-alkyl,halo-C₁-C₆-alkyl, halogen-substituted carbocyclyl-C₁-C₆-alkyl, orhalogen-substituted heterocyclyl-C₁-C₆-alkyl.

In some preferred embodiments, R⁸ is —H, C₁-C₆-alkyl, —O—R⁹,—N(R⁹)(R¹⁰), carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl.

R⁹ and R¹⁰ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl,heterocyclyl-C₁-C₈-alkyl, halo-C₁-C₈-alkyl, halocarbocyclyl,halogen-substituted carbocyclyl-C₁-C₈-alkyl, haloheterocyclyl, andhalogen-substituted heterocyclyl-C₁-C₈-alkyl.

In some preferred embodiments, R⁹ and R¹⁰ are independently selectedfrom the group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, heterocyclyl-C₁-C₆-alkyl,halo-C₁-C₆-alkyl, halocarbocyclyl, halogen-substitutedcarbocyclyl-C₁-C₆-alkyl, haloheterocyclyl, and halogen-substitutedheterocyclyl-C₁-C₆-alkyl.

In some preferred embodiments, R⁹ and R¹⁰ are independently selectedfrom the group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, and heterocyclyl, heterocyclyl-C₁-C₆-alkyl.

Preferred Embodiment No. 2-a: E³ is optionally-substituted heterocyclyl

In some embodiments, E³ is optionally-substituted heterocyclyl.

In some preferred embodiments E³ is an optionally-substitutedheterocyclyl that contains only one heteroatom ring member. Examples ofoften suitable heterocyclyls include furanyl, tetrahydropyranyl,dihydrofuranyl, tetrahydrofuranyl, thiophenyl, dihydrothiophenyl,tetrahydrothiophenyl, pyrrolinyl, pyrrolyl, isopyrrolyl, pyrrolidinyl,pyridinyl, piperidinyl, pyranyl, dihydropyranyl, and tetrahydropyranyl.

In some preferred embodiments, E³ is optionally-substituted pyridinyl.In some such embodiments, E⁵ is optionally-substituted phenyl. Suchcompounds include, for example:

Such compounds also include, for example:

In some preferred embodiments, E³ is an optionally-substitutedheterocyclyl selected from the group consisting of:

Any member of this group optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,carbocyclyl, carbocyclyl-C₁-C₆-alkyl, heterocyclyl, andheterocyclyl-C₁-C₆-alkyl. Except where the substituent is halogen or—OH, any substituent of this group optionally is substituted with one ormore substituents independently selected from the group consisting ofhalogen, —OH, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-alkylthio, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy,halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl, and halo-C₁-C₆-alkylthio.R¹⁴ is selected from the group consisting of halogen, —OH, C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is halogen or —OH, any member of this groupoptionally is substituted with one or more substituents independentlyselected from the group consisting of halogen, —OH, C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio,halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, halogen-substitutedC₁-C₆-alkoxy-C₁-C₆-alkyl, and halo-C₁-C₆-alkylthio.

In some preferred embodiments, E³ is optionally-substituted furanyl. Inone such embodiment, for example, E⁵ is optionally-substituted phenyl.Such compounds include, for example:

In some preferred embodiments, E³ is optionally-substituted thienyl. Insome such embodiments, E⁵ is optionally-substituted phenyl. Suchcompounds include, for example:

Such compounds also include, for example:

In some preferred embodiments, E³ is optionally-substitutedpyrrolidinyl. In some such embodiments, for example, E⁵ isoptionally-substituted phenyl. Such compounds include, for example:

E³ also may be, for example, an optionally-substituted heterocyclyl thatcontains no greater and no less than two heteroatom ring members.Suitable heterocyclyls include, for example, pyrazolyl, pyrazolinyl,pyrazolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl,dithiolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl,thiazolidinyl, isothiazolidinyl, oxathiolyl, oxathiolanyl, oxazolyl,isoxazolyl, oxazolidinyl, isoxazolidinyl, pyrazinyl, piperazinyl,pyrimidinyl, pyridazinyl, oxazinyl, and morpholinyl.

In some preferred embodiments, E³ is an optionally-substitutedheterocyclyl selected from the group consisting of:

Any member of this group optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,carbocyclyl, carbocyclyl-C₁-C₆-alkyl, heterocyclyl, andheterocyclyl-C₁-C₆-alkyl. Except where the substituent is halogen or—OH, any substituent of this group optionally is substituted with one ormore substituents independently selected from the group consisting ofhalogen, —OH, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-alkylthio, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy,halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl, and halo-C₁-C₆-alkylthio.Such substituents also optionally are substituted with one or moresubstituents independently selected from the group consisting ofC₂-C₆-alkenyl and C₂-C₆-alkynyl. R¹⁴ is as defined above where E³contains only one heteroatom in its ring.

In some particularly preferred embodiments, E³ is anoptionally-substituted heterocyclyl selected from the group consistingof oxazolyl and isoxazolyl. In some such embodiment, for example, E⁵ isoptionally-substituted carbocyclyl, often preferablyoptionally-substituted aryl, and more preferably optionally-substitutedphenyl. Such compounds include, for example:

In some preferred embodiments, E³ is an optionally-substitutedheteroaryl selected from the group consisting of pyrazolyl andisoimidazolyl. In some such embodiments, E⁵ is optionally-substitutedcarbocyclyl, often preferably optionally-substituted aryl, and morepreferably optionally-substituted phenyl. Such compounds include, forexample:

In some preferred embodiments, E³ is an optionally-substitutedheteroaryl selected from the group consisting of thiazolyl andisothiazolyl. In one such embodiment, for example, E⁵ isoptionally-substituted carbocyclyl, often preferablyoptionally-substituted aryl, and more preferably optionally-substitutedphenyl. Such compounds include, for example:

In some preferred embodiments, E³ is an optionally-substitutedheteroaryl selected from the group consisting of pyrazolidinyl andimidazolidinyl. In some such embodiments, E⁵ is optionally-substitutedcarbocyclyl. In some preferred embodiments, E⁵ is optionally-substitutedaryl, often preferably optionally-substituted phenyl. Such compoundsinclude, for example:

In other preferred embodiments, E⁵ is optionally substitutedC₅-C₆-cycloalkyl. Such compounds include, for example:

In some preferred embodiments, E³ is optionally-substitutedoxazolidinyl. In some such embodiments, E⁵ is optionally-substitutedcarbocyclyl, often preferably optionally-substituted aryl, and morepreferably optionally-substituted phenyl. Such compounds include, forexample:

E³ also may be, for example, an optionally-substituted heterocyclyl thatcontains no greater and no less than 3 heteroatom ring members. Oftensuitable heterocyclyls include, for example, oxadiazolyl, thiadiazolyl,and triazolyl. Here, the triazolyl optionally is substituted.

In some preferred embodiments, E³ is an optionally-substitutedheteroaryl selected from the group consisting of:

Any member of this group optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,carbocyclyl, carbocyclyl-C₁-C₆-alkyl, heterocyclyl, andheterocyclyl-C₁-C₆-alkyl. Except where the substituent is halogen or—OH, any substituent of this group optionally is substituted with one ormore substituents independently selected from the group consisting ofhalogen, —OH, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,C₁-C₆-alkylthio, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy,halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl, and halo-C₁-C₆-alkylthio.R¹⁴ is as defined above for heterocyclyls containing 1 or 2 heteroatomring members.

In some preferred embodiments, E³ is oxadiazolyl.

In some such embodiments, E⁵ is optionally-substituted phenyl. Suchcompounds include, for example:

Such compounds also include, for example:

In other embodiments, E⁵ is optionally-substituted naphthalenyl. Suchcompounds include, for example:

In other embodiments, E⁵ is optionally-substituted C₅-C₆-cycloalkyl.Such compounds include, for example:

In yet other embodiments, E⁵ is optionally-substituted heterocyclyl.Such compounds include, for example:

Such compounds also include, for example:

E³ also may be, for example, an optionally-substituted heterocyclyl thatcontains at least 4 heteroatom ring members.

In some preferred embodiments, E³ is selected from the group consistingof:

In some such embodiments, E⁵ is optionally-substituted carbocyclyl,often preferably optionally-substituted aryl, and more preferablyoptionally-substituted phenyl. Such compounds include, for example:

In other such embodiments, E⁵ is optionally-substituted heterocyclyl.Such compounds include, for example:

Preferred Embodiment No. 2-b: E³ is optionally substituted carbocyclyl

In some embodiments, E³ is an optionally-substituted carbocyclyl. E³ maybe, for example, an optionally-substituted carbocyclyl selected from thegroup consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl,naphthalenyl, tetrahydronaphthalenyl, indenyl, isoindenyl, indanyl,bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl, fluoreneyl,decalinyl, and norpinanyl.

In some preferred embodiments, E³ is optionally-substituted phenyl. Inone such embodiment, for example, E⁵ is optionally-substitutedheterocyclyl.

In some such embodiments, E⁵ is optionally-substituted heterocycloalkyl.Examples of such compounds include, for example:

In other preferred embodiments, E⁵ is optionally-substituted, 5-memberheteroaryl. Examples of such compounds include, for example:

Such compounds also include, for example:

In other preferred embodiments, E⁵ is optionally-substituted, 6-memberheteroaryl.

In other preferred embodiments, E⁵ is optionally-substituted pyridinyl.Such compounds include, for example:

Such compounds also include, for example:

In other preferred embodiments, E⁵ is optionally-substitutedpyrimidinyl. Such compounds include, for example:

In other preferred embodiments, E⁵ is optionally-substituted, multi-ringheterocyclyl. Such compounds include, for example:

In some preferred embodiments, for example, E⁵ is optionally-substitutedcarbocyclyl, often preferably optionally-substituted aryl,

In some preferred embodiments, E⁵ is optionally-substituted phenyl. Suchcompounds include, for example:

Other such compounds include, for example:

In other preferred embodiments, E⁵ is optionally-substitutednaphthalenyl. Such compounds include, for example:

Preferred Embodiment No. 3

In some embodiments of this invention, the compound has a structurecorresponding to Formula IV:

A¹, A², and A³ are as defined above for Formula I.

E¹ is s —O—, —S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—, or—C(R¹)(R²)—.

E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, oralkylcycloalkylalkyl. Any member of this group optionally issubstituted.

In some preferred embodiments, E² is C₁-C₂₀-alkyl, cycloalkyl,C₁-C₁₀-alkylcycloalkyl, cycloalkyl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkylcycloalkyl-C₁-C₁₀-alkyl. Any member of this group optionallyis substituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, E² is C₁-C₆-alkyl, cycloalkyl,C₁-C₆-alkylcycloalkyl, cycloalkyl-C₁-C₆-alkyl, orC₁-C₆-alkylcycloalkyl-C₁-C₆-alkyl. Any member of this group optionallyis substituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₂-alkyl, and halo-C₁-C₂-alkyl.

In some preferred embodiments, E² is C₁-C₆-alkyl, cycloalkyl,C₁-C₆-alkylcycloalkyl, cycloalkyl-C₁-C₆-alkyl, orC₁-C₆-alkylcycloalkyl-C₁-C₆-alkyl. Any member of this group optionallyis substituted with one or more C₁-C₂-alkyl.

E⁴ is a bond or alkyl. The alkyl optionally is substituted.

In some preferred embodiments, E⁴ is a bond, C₁-C₂₀-alkyl, orhalo-C₁-C₂₀-alkyl.

In some preferred embodiments, E⁴ is a bond, C₁-C₃-alkyl, orhalo-C₁-C₃-alkyl.

In some preferred embodiments, E⁴ is a bond or C₁-C₃-alkyl.

In some preferred embodiments, E⁴ is a bond.

E⁵ is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, orheterocyclyl. Any member of this group optionally is substituted.

In some preferred embodiments, E⁵ is C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl,C₂-C₂₀-alkynyl, C₁-C₂₀-alkoxy, C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl, carbocyclyl,or heterocyclyl. The C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, C₂-C₂₀-alkynyl,C₁-C₂₀-alkoxy, and C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl optionally are substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, and —CN. The carbocyclyl andheterocyclyl optionally are substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH, —NO₂,—CN, keto, C₁-C₈-alkyl, halo-C₁-C₈-alkyl, C₁-C₈-alkoxy,C₁-C₈-alkoxy-C₁-C₈-alkyl, halo-C₁-C₈-alkoxy, —N(R⁷)(R⁸), —C(O)(R⁹),—S—R⁷, —S(O)₂—R⁷, carbocyclyl, halocarbocyclyl, carbocyclyl-C₁-C₈-alkyl,and halogen-substituted C₁-C₈-alkoxy-C₁-C₈-alkyl.

In some preferred embodiments, E⁵ is C₁-C₈-alkyl, C₂-C₈-alkenyl,C₂-C₈-alkynyl, C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl, carbocyclyl, orheterocyclyl. The C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl,C₁-C₈-alkoxy, and C₁-C₈-alkoxy-C₁-C₈-alkyl optionally are substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, and —CN. The carbocyclyl andheterocyclyl optionally are substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH, —NO₂,—CN, keto, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, —N(R⁷)(R⁸), —C(O)(R⁹),—S—R⁷, —S(O)₂—R⁷, carbocyclyl, halocarbocyclyl, carbocyclyl-C₁-C₆-alkyl,and halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl.

E⁶ is —H, halogen, or alkyl. The alkyl optionally is substituted.

In some preferred embodiments, E⁶ is —H, halogen, or C₁-C₈-alkyl. TheC₁-C₈-alkyl may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, E⁶ is —H, halogen, or C₁-C₆-alkyl. TheC₁-C₆-alkyl may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

E⁷ is —H, alkyl, alkenyl, alkynyl, —S(O)₂—R³, —NO₂, —C(O)—N(R³)(R⁴),—(C)(OR³), carbocyclyl, carbocyclylalkyl, alkoxycarbocyclyl, —CN,—C═N—OH, or —C═NH. The alkyl, alkenyl, alkynyl, carbocyclyl,carbocyclylalkyl, and alkoxycarbocyclyl optionally are substituted.

In some preferred embodiments, E⁷ is —H, C₁-C₈-alkyl, C₁-C₈-alkenyl,C₁-C₈-alkynyl, —S(O)₂—R³, —NO², —C(O)—N(R³)(R⁴), —(C)(OR³), carbocyclyl,carbocycyl-C₁-C₈-alkyl, C₁-C₈-alkoxycarbocyclyl, —CN, —C═N—OH, or —C═NH.The C₁-C₆-alkyl, C₁-C₈-alkenyl, C₁-C₈-alkynyl, carbocyclyl,carbocycyl-C₁-C₈-alkyl, or C₁-C₆-alkoxycarbocyclyl may be substitutedwith one or more halogen, but more typically is preferably notsubstituted with halogen.

In some preferred embodiments, E⁷ is —H, C₁-C₆-alkyl, C₁-C₆-alkenyl,C₁-C₆-alkynyl, —S(O)₂—R³, —NO₂, —C(O)—N(R³)(R⁴), —(C)(OR³), carbocyclyl,carbocycyl-C₁-C₆-alkyl, C₁-C₆-alkoxycarbocyclyl, —CN, —C═N—OH, or —C═NH.The C₁-C₆-alkyl, C₁-C₆-alkenyl, C₁-C₆-alkynyl, carbocyclyl,carbocycyl-C₁-C₆-alkyl, or C₁-C₆-alkoxycarbocyclyl may be substitutedwith one or more halogen, but more typically is preferably notsubstituted with halogen.

R¹ and R² are independently selected from the group consisting of —H andalkyl. The alkyl optionally is substituted. Neither R¹ nor R² forms aring structure with E², E⁴, E⁵, E⁶, or E⁷.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, and halo-C₁-C₈-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H and C₁-C₆-alkyl.

R³ and R⁴ are independently selected from the group consisting of —H,alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, andheterocyclylalkyl. Except where the member is —H, any member of thisgroup optionally is substituted.

In some preferred embodiments, R³ and R⁴ are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, carbocyclyl,carbocyclyl-C₁-C₈-alkyl, heterocyclyl, and heterocyclyl-C₁-C₈-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, R³ and R⁴ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R⁷ and R⁸ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁷ and R⁸ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R⁹ is —H, C₁-C₈-alkyl, —O—R¹⁰, —N(R¹⁰)(R¹¹), carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl. The C₁-C₈-alkyl,carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl may be substituted with one or more halogen,but more typically is preferably not substituted with halogen.

In some preferred embodiments, R⁹ is —H, C₁-C₆-alkyl, —O—R¹⁰,—N(R¹⁰)(R¹¹), carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl. TheC₁-C₆-alkyl, carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R¹⁰ and R¹¹ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R¹⁰ and R¹¹ are independently selectedfrom the group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, E⁵ is optionally-substituted carbocyclylor optionally-substituted heterocyclyl. For example, in some suchembodiments, E⁵ is optionally-substituted carbocyclyl, often preferablyoptionally-substituted aryl, and more preferably optionally-substitutedphenyl. Such compounds include, for example:

In some preferred embodiments, E⁵ is C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, C₁-C₆-alkoxy, or C₁-C₆-alkoxy-C₁-C₆-alkyl. Any member ofthis group optionally is substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH, —NO₂,and —CN.

In some preferred embodiments, E⁵ is optionally-substituted C₁-C₆-alkyl,with the C₁-C₆-alkyl often being more preferably unsubstituted. Suchcompounds include, for example:

Preferred Embodiment No. 4

In some embodiments of this invention, the compound has a structurecorresponding to Formula V:

A¹, A², and A³ are as defined above for Formula I.

E¹ is —O—, —S(O)₂—, —S(O)—, —N(R³)—, —C(O)—N(R³)—, —N(R³)—C(O)—, or—C(R¹)(R²)—.

E² is a bond, alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, oralkylcycloalkylalkyl. Except where the member is a bond, any member ofsuch group optionally is substituted.

In some preferred embodiments, E² is a bond, C₁-C₂₀-alkyl, cycloalkyl,C₁-C₁₀-alkylcycloalkyl, cycloalkyl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkylcycloalkyl-C₁-C₁₀)-alkyl. Any member of this group (exceptfor the bond) optionally is substituted with one or more substituentsindependently selected from the group consisting of halogen,C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, E² is a bond, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl.

In some preferred embodiments E² is a bond or C₁-C₆-alkyl.

E³ is carbonylpyrrollidinyl. The carbonylpyrrollidinyl optionally issubstituted.

In some preferred embodiments, E³ is carbonylpyrrollidinyl wherein thecarbonylpyrrollidinyl may be substituted with one or more halogen, butmore typically is preferably not substituted with halogen.

E⁴ is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally aresubstituted.

In some preferred embodiments, E⁴ is a bond, C₁-C₂₀-alkyl,halo-C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, or halo-C₂-C₂₀-alkenyl.

In some preferred embodiments, E⁴ is a bond, C₁-C₃-alkyl,halo-C₁-C₃-alkyl, C₂-C₃-alkenyl, or halo-C₂-C₃-alkenyl.

In some preferred embodiments, E⁴ is a bond, C₁-C₃-alkyl, orC₂-C₃-alkenyl.

In some preferred embodiments, E⁴ is a bond.

E⁵ is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, orheterocyclyl. Any member of this group optionally is substituted.

In some preferred embodiments, E⁵ is C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl,C₂-C₂₀-alkynyl, C₁-C₂₀-alkoxy, C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl, carbocyclyl,or heterocyclyl. The C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, C₂-C₂₀-alkynyl,C₁-C₂₀-alkoxy, and C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl optionally are substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, and —CN. The carbocyclyl andheterocyclyl optionally are substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH, —NO₂,—CN, keto, C₁-C₈-alkyl, halo-C₁-C₈-alkyl, C₁-C₈-alkoxy,halo-C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₆-alkyl, halogen-substitutedC₁-C₈-alkoxy-C₁-C₈-alkyl, —N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵,carbocyclyl, halocarbocyclyl, carbocyclyl-C₁-C₈-alkyl, andhalogen-substituted carbocyclyl-C₁-C₈-alkyl.

In some preferred embodiments, E⁵ is C₁-C₈-alkyl, C₂-C₈-alkenyl,C₂-C₈-alkynyl, C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl, carbocyclyl, orheterocyclyl. The C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl,C₁-C₈-alkoxy, and C₁-C₈-alkoxy-C₁-C₈-alkyl optionally are substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, and —CN. The carbocyclyl andheterocyclyl optionally are substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH, —NO₂,—CN, keto, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy,halo-C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, halogen-substitutedC₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵,carbocyclyl, halocarbocyclyl, carbocyclyl-C₁-C₆-alkyl, andhalogen-substituted carbocyclyl-C₁-C₆-alkyl.

R¹ and R² are independently selected from the group consisting of —H andalkyl. The alkyl optionally is substituted. Neither R¹ nor R² forms aring structure with E², E³, E⁴, or E⁵.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H and C₁-C₆-alkyl.

R⁵ and R⁶ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁵ and R⁶ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R⁷ is —H, C₁-C₈-alkyl, —O—R⁸, —N(R⁸)(R⁹), carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl. The C₁-C₈-alkyl, carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl may be substituted with one or more halogen,but more typically is preferably not substituted with halogen.

In some preferred embodiments, R⁷ is —H, C₁-C₆-alkyl, —O—R⁸, —N(R⁸)(R⁹),carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl. The C₁-C₆-alkyl,carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl may be substitutedwith one or more halogen, but more typically is preferably notsubstituted with halogen.

R⁸ and R⁹ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁸ and R⁹ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, the compound has a structurecorresponding to Formula V-A:

In some preferred embodiments, E⁵ is optionally-substituted carbocyclylor optionally substituted heterocyclyl. For example, in some suchembodiments, E⁵ is optionally substituted carbocyclyl, often preferablyoptionally-substituted aryl, and more preferably optionally-substitutedphenyl. Such compounds include, for example:

In some preferred embodiments, E⁵ is optionally-substitutedC₅-C₆-Cycloalkyl. Such compounds include, for example:

In some preferred embodiments, E⁵ is C₁-C₈-alkyl, C₂-C₈-alkenyl,C₂-C₈-alkynyl, C₁-C₈-alkoxy, or C₁-C₈-alkoxy-C₁-C₈-alkyl. TheC₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₁-C₈-alkoxy, andC₁-C₈-alkoxy-C₁-C₈-alkyl optionally are substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO₂, and —CN.

In some preferred embodiments, E⁵ is optionally-substituted C₁-C₈-alkyl,with C₁-C₈-alkyl often being more preferred. Such compounds include, forexample:

Preferred Embodiment No. 5

In some embodiments of this invention, the compound has a structurecorresponding to Formula VI:

A¹, A², and A³ are as defined above for Formula I.

E¹ is —O—, —S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—, or—C(R¹)(R²).

E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, oralkylcycloalkylalkyl. Any member of this group optionally is substitutedwith one or more substituents independently selected from the groupconsisting of halogen, alkyl, and haloalkyl.

In some preferred embodiments, E² is C₁-C₂₀-alkyl, cycloalkyl,C₁-C₁₀-alkylcycloalkyl, cycloalkyl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkylcycloalkyl-C₁-C₁₀-alkyl. Any member of this group optionallyis substituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, E² is C₁-C₆-alkyl, cycloalkyl,C₁-C₆-alkylcycloalkyl, cycloalkyl-C₁-C₆-alkyl, orC₁-C₆-alkylcycloalkyl-C₁-C₆-alkyl. Any member of this group optionallyis substituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₂-alkyl, and halo-C₁-C₂-alkyl.

In some preferred embodiments, E² is C₁-C₆-alkyl, cycloalkyl,C₁-C₆-alkylcycloalkyl, cycloalkyl-C₁-C₆-alkyl, orC₁-C₆-alkylcycloalkyl-C₁-C₆-alkyl. Any member of this group optionallyis substituted with one or more C₁-C₂-alkyl.

E⁵ is alkyl, alkenyl, alkynyl, cycloalkyl, cyclopentenyl,cyclopentadienyl, cyclohexenyl, or cyclohexadienyl. Here, thecycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, andcyclohexadienyl optionally are substituted. The alkyl, alkenyl, andalkynyl (a) contain at least 4 carbon atoms, and (b) optionally aresubstituted with one or more substituents selected from the groupconsisting of —OH, —NO₂, —CN, and halogen.

In some preferred embodiments, E⁵ is C₄-C₂₀-alkyl, C₄-C₂₀-alkenyl,C₄-C₂₀-alkynyl, cycloalkyl, cyclopentenyl, cyclopentadienyl,cyclohexenyl, or cyclohexadienyl. The C₄-C₂₀-alkyl, C₄-C₂₀-alkenyl, andC₄-C₂₀-alkynyl optionally are substituted with one or more substituentsindependently selected from the group consisting of —OH, —NO₂, —CN, andhalogen. The cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,and cyclohexadienyl optionally are substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO₂, —CN, keto, C₁-C₈-alkyl, halo-C₁-C₈-alkyl,C₁-C₈-alkoxy, halo-C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl,halogen-substituted C₁-C₈-alkoxy-C₁-C₈-alkyl, —N(R⁵)(R⁶), —C(O)(R⁷),—S—R⁵, —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl, carbocyclyl-C₁-C₈-alkyl,and halogen-substituted carbocyclyl-C₁-C₈-alkyl.

In some preferred embodiments, E⁵ is C₄-C₈-alkyl, C₄-C₈-alkenyl,C₄-C₈-alkynyl, cycloalkyl, cyclopentenyl, cyclopentadienyl,cyclohexenyl, or cyclohexadienyl. The C₄-C₈-alkyl, C₄-C₈-alkenyl, andC₄-C₈-alkynyl optionally are substituted with one or more substituentsindependently selected from the group consisting of —OH, —NO₂, —CN, andhalogen. The cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,and cyclohexadienyl optionally are substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO2, —CN, keto, C₁-C₆-alkyl, halo-C₁-C₆-alkyl,C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R⁵)(R⁶), —C(O)(R⁷),—S—R⁵, —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl, carbocyclyl-C₁-C₆-alkyl,and halogen-substituted carbocyclyl-C₁-C₆-alkyl.

R¹ and R² are independently selected from the group consisting of —H andalkyl. The alkyl optionally is substituted. Neither R¹ nor R² forms aring structure with E⁵.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, and halo-C₁-C₈-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H and C₁-C₆-alkyl.

R⁵ and R⁶ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁵ and R⁶ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R⁷ is —H, C₁-C₈-alkyl, —O—R⁸, —N(R⁸)(R⁹), carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl. The C₁-C₈-alkyl, carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl maybe substituted with one or more halogen, butmore typically is preferably not substituted with halogen.

In some preferred embodiments, R⁷ is —H, C₁-C₆-alkyl, —O—R⁸, —N(R⁸)(R⁹),carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl. The C₁-C₆-alkyl,carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl may be substitutedwith one or more halogen, but more typically is preferably notsubstituted with halogen.

R⁸ and R⁹ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁸ and R⁹ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, E⁵ is C₄-C₈-alkyl, C₄-C₈-alkenyl, orC₄-C₈-alkynyl. The C₄-C₈-alkyl, C₄-C₈-alkenyl, and C₄-C₈-alkynyloptionally are substituted with one or more substituents independentlyselected from the group consisting of —OH, —NO₂, —CN, and halogen. Suchcompounds include, for example:

In some preferred embodiments, E⁵ is optionally-substituted carbocyclyl.In some such embodiments, E⁵ is optionally-substituted C₅-C₆-cycloalkyl.Such compounds include, for example:

In other such embodiments, E⁵ is an optionally-substituted,partially-saturated carbocyclyl selected from the group consisting ofcyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl. Suchcompounds include, for example:

Preferred Embodiment No. 6

In some embodiments of this invention, the compound has a structurecorresponding to Formula VII:

A¹, A², and A³ are as defined above for Formula I.

E¹ is —O—, —S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—, or—C(R¹)(R²)—.

E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, oralkylcycloalkyl. Any member of this group optionally is substituted.

In some preferred embodiments, E² is C₁-C₂₀-alkyl, cycloalkyl,C₁-C₁₀-alkylcycloalkyl, cycloalkyl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkylcycloalkyl-C₁-C₁₀-alkyl. Any member of this group optionallyis substituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, E² is C₁-C₆-alkyl optionally substitutedwith one or more halogen.

In some preferred embodiments, E² is C₁-C₆-alkyl.

E³ is carbonylpiperidinyl. The carbonylpiperidinyl optionally issubstituted.

In some preferred embodiments, E³ is carbonylpiperidinyl wherein thecarbonylpiperidinyl may be substituted with one or more halogen, butmore typically is preferably not substituted with halogen.

In some preferred embodiments, the compound has a structurecorresponding to one of the following formulas:

E⁴ is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally aresubstituted.

In some preferred embodiments, E⁴ is a bond, C₁-C₂₀-alkyl,halo-C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, or halo-C₂-C₂₀-alkenyl.

In some preferred embodiments, E⁴ is a bond, C₁-C₃-alkyl,halo-C₁-C₃-alkyl, C₂-C₃-alkenyl, or halo-C₂-C₃-alkenyl.

In some preferred embodiments, E⁴ is a bond, C₁-C₃-alkyl, orC₂-C₃-alkenyl.

In some preferred embodiments, E⁴ is a bond.

E⁵ is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, orheterocyclyl. Any member of this group optionally is substituted.

In some preferred embodiments, E⁵ is C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl,C₂-C₂₀-alkynyl, C₁-C₂₀-alkoxy, C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl, carbocyclyl,or heterocyclyl. The C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, C₂-C₂₀-alkynyl,C₁-C₂₀-alkoxy, and C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl optionally are substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, and —CN. The carbocyclyl andheterocyclyl optionally are substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH, —NO₂,—CN, keto, C₁-C₈-alkyl, halo-C₁-C₈-alkyl, C₁-C₈-alkoxy,halo-C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl, halogen-substitutedC₁-C₈-alkoxy-C₁-C₈-alkyl, —N(R)(R⁶), —C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵,carbocyclyl, halocarbocyclyl, and carbocyclyl-C₁-C₈-alkyl.

In some preferred embodiments, E⁵ is C₁-C₈-alkyl, C₂-C₈-alkenyl,C₂-C₈-alkynyl, C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl, carbocyclyl, orheterocyclyl. Here, the C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl,C₁-C₈-alkoxy, and C₁-C₆-alkoxy-C₁-C₆-alkyl optionally are substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, and —CN. The carbocyclyl andheterocyclyl optionally are substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH, —NO₂,—CN, keto, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy,halo-C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, halogen-substitutedC₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵,carbocyclyl, halocarbocyclyl, carbocyclyl-C₁-C₆-alkyl, andhalogen-substituted carbocyclyl-C₁-C₆-alkyl.

R¹ and R² are independently selected from the group consisting of —H andalkyl. The alkyl optionally is substituted. Neither R¹ nor R² forms aring structure with E², E³, E⁴, or E⁵.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H and C₁-C₆-alkyl.

R¹ and R⁶ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁵ and R⁶ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R⁷ is —H, C₁-C₆-alkyl, —O—R⁸, —N(R⁸)(R⁹), carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl. The C₁-C₈-alkyl, carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl may be substituted with one or more halogen,but more typically is preferably not substituted with halogen.

In some preferred embodiments, R⁷ is —H, C₁-C₆-alkyl, —O—R⁸, —N(R⁸)(R⁹),carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl. The C₁-C₆-alkyl,carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl may be substitutedwith one or more halogen, but more typically is preferably notsubstituted with halogen.

R⁸ and R⁹ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁸ and R⁹ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, E⁵ is optionally-substituted carbocyclylor optionally substituted heterocyclyl. In some such embodiments, E⁵ isoptionally-substituted aryl, often preferably optionally-substitutedphenyl. Such compounds include, for example:

Preferred Embodiment No. 7

In some embodiments of this invention, the compound has a structurecorresponding to Formula VIII:

A¹, A², and A³ are as defined above for Formula I.

E¹ is —O—, —S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—, or—C(R¹)(R²)—.

E² forms a link of at least 3 carbon atoms between E¹ and E⁵. E² isalkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, oralkylcycloalkylalkyl. Any member of this group optionally issubstituted.

In some preferred embodiments, E² is C₃-C₂₀-alkyl, cycloalkyl,C₁-C₁₀-alkyl-cycloalkyl, cycloalkyl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkyl-cycloalkyl-C₁-C₁₀-alkyl. Any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, E² is C₃-C₆-alkyl optionally substitutedwith one or more halogen.

In some preferred embodiments, E² is C₃-C₆-alkyl.

E⁵ is optionally-substituted heterocyclyl, optionally-substitutedfused-ring carbocyclyl, or substituted single-ring carbocyclyl.

In some preferred embodiments, E⁵ is single-ring carbocyclyl, fused-ringcarbocyclyl, or heterocyclyl.

Here, the single-ring carbocyclyl is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO₂, —CN, keto, C₁-C₈-alkyl, halo-C₁-C₈-alkyl,C₁-C₈-alkoxy, halo-C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl,halogen-substituted C₁-C₈-alkoxy-C₁-C₈-alkyl, —N(R⁵)(R⁶), —C(O)(R⁷),—S—R⁵, —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl, carbocyclyl-C₁-C₈-alkyl,halogen-substituted carbocyclyl-C₁-C₈-alkyl. The single-ring carbocyclylalso optionally is substituted on the same atom with two substituentsindependently selected from the group consisting of alkyl and haloalkyl,the two substituents together forming C₅-C₆-Cycloalkyl orhalo-C₅-C₆-Cycloalkyl.

In some preferred embodiments, the single-ring carbocyclyl issubstituted with one or more substituents independently selected fromthe group consisting of and halogen, —OH, —NO₂, —CN, keto, C₁-C₆-alkyl,halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl,—N⁵)(R⁶), —C(O)(⁷), —S—R⁵, —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl,carbocyclyl-C₁-C₆-alkyl, and halogen-substitutedcarbocyclyl-C₁-C₆-alkyl. The single-ring carbocyclyl also optionally issubstituted on the same atom with two substituents independentlyselected from the group consisting of alkyl and haloalkyl, the twosubstituents together forming C₅-C₆-Cycloalkyl or halo-C₅-C₆-Cycloalkyl.

The heterocyclyl and fused-ring carbocyclyl optionally are substitutedwith one or more substituents independently selected from the groupconsisting of and halogen, —OH, —NO₂, —CN, keto, C₁-C₈-alkyl,halo-C₁-C₈-alkyl, C₁-C₈-alkoxy, halo-C₁-C₈-alkoxy,C₁-C₈-alkoxy-C₁-C₈-alkyl, halogen-substituted C₁-C₈-alkoxy-C₁-C₈-alkyl,—N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl,and carbocyclyl-C₁-C₆-alkyl. The heterocyclyl and fused-ring carbocyclylalso optionally are substituted on the same atom with two substituentsindependently selected from the group consisting of alkyl and haloalkyl,the two substituents together forming C₅-C₆-Cycloalkyl orhalo-C₅-C₆-Cycloalkyl.

In some preferred embodiments, the heterocyclyl and fused-ringcarbocyclyl optionally are substituted with one or more substituentsindependently selected from the group consisting of and halogen, —OH,—NO₂, —CN, keto, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy,halo-C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, halogen-substitutedC₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R⁵)(R⁶), —C(O)(⁷), —S—R⁵, —S(O)₂—R⁵,carbocyclyl, halocarbocyclyl, carbocyclyl-C₁-C₆-alkyl, andhalogen-substituted carbocyclyl-C₁-C₆-alkyl. The heterocyclyl andfused-ring carbocyclyl also optionally are substituted on the same atomwith two substituents independently selected from the group consistingof alkyl and haloalkyl, the two substituents together formingC₅-C₆-Cycloalkyl or halo-C₅-C₆-Cycloalkyl.

R¹ and R² are independently selected from the group consisting of —H andalkyl. The alkyl optionally is substituted. Neither R¹ nor R² forms aring structure with E⁵.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, and halo-C₁-C₈-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H and C₁-C₆-alkyl.

R⁵ and R⁶ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁵ and R⁶ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R⁷ is —H, C₁-C₈-alkyl, —O—R⁸, —N(R⁸)(R⁹), carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl. The C₁-C₈-alkyl, carbocyclyl C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl may be substituted with one or more halogen,but more typically is preferably not substituted with halogen.

In some preferred embodiments, R⁷ is —H, C₁-C₆-alkyl, —O—R⁸, —N(R⁸)(R⁹),carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl. The C₁-C₆-alkyl,carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl may be substitutedwith one or more halogen, but more typically is preferably notsubstituted with halogen.

R⁸ and R⁹ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁸ and R⁹ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, E⁵ is a substituted single-ringcarbocyclyl. E⁵ may be, for example a substituted single-ringcarbocyclyl selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl,cyclohexenyl, cyclobexadienyl, and phenyl.

In some preferred embodiments, E⁵ is substituted phenyl. Such compoundsinclude, for example:

Such compounds also include, for example:

In some preferred embodiments, E⁵ is optionally-substituted fused-ringcarbocyclyl. E⁵ may be, for example, optionally-substituted fused-ringcarbocyclyl selected from the group consisting of naphthalenyl,tetrahydronaphthalenyl, indenyl, isoindenyl, indanyl, bicyclodecanyl,anthracenyl, phenanthrene, benzonaphthenyl, fluoreneyl, decalinyl, andnorpinanyl.

In some preferred embodiments, E⁵ is optionally-substitutednaphthalenyl. Such compounds include, for example:

In some preferred embodiments, E⁵ is optionally-substituted, single-ringheterocyclyl.

In some preferred embodiments, E⁵ is an optionally-substitutedpyridinyl. Such compounds include, for example:

In some preferred embodiments, E⁵ is an optionally-substitutedheterocyclyl selected from the group consisting of imidazolyl,imidazolinyl, imidazolidinyl, pyrazoly), pyrazolinyl, and pyrazolidinyl.Such compounds include, for example:

In some preferred embodiments, E⁵ is optionally-substituted fused-ringheterocyclyl. E⁵ may be, for example, an optionally-substitutedfused-ring heterocyclyl selected from the group consisting ofindolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl,naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl,indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl,quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl,benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl,benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl,isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl,benzotriazolyl, benzoxazinyl, benzisoxazinyl, tetrahydroisoquinolinyl,carbazolyl, xanthenyl, and acridinyl. Compounds wherein E⁵ is anoptionally-substituted fused-ring heterocyclyl include, for example:

In some preferred embodiments, E⁵ is optionally-substitutedtetrahydroisoquinolinyl. Such compounds include, for example:

In some preferred embodiments, E⁵ is heterocyclyl that is substituted onthe same atom with two substituents independently selected from thegroup consisting of alkyl and haloalkyl, the two substituents togetherforming C₅-C₆-Cycloalkyl or halo-C₅-C₆-Cycloalkyl. This heterocyclylalso optionally is substituted with one or more substituentsindependently selected from the group consisting of and halogen, —OH,—NO₂, —CN, keto, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy,halo-C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, halogen-substitutedC₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵, —S(O—R⁵,carbocyclyl, halocarbocyclyl, carbocyclyl-C₁-C₆-alkyl, andhalogen-substituted carbocyclyl-C₁-C₆-alkyl. The heterocyclyl that issubstituted may be, for example, selected from the group consisting ofdihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl,tetrahydrothiophenyl, pyrrolinyl, pyrrolidinyl, imidazolinyl,imidazolidinyl, pyrazolinyl, pyrazolidinyl, dithiolyl, oxathiolyl,thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl,oxathiolanyl, pyranyl, dihydropyranyl, piperidinyl, piperazinyl, andmorpholinyl. Such compounds include, for example:

Preferred Embodiment No. 8

In some embodiments of this invention, the compound has a structurecorresponding to Formula IX:

A¹, A², and A³ are as defined above for Formula I.

E¹ is —O—, —S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)C(O)—, or—C(R¹)(R²)—.

E² forms a link of at least 4 carbon atoms between E¹ and E⁵. E² isalkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, oralkylcycloalkylalkyl. Any member of this group optionally issubstituted.

In some preferred embodiments, E² is C₄-C₂₀-alkyl, cycloalkyl,C₁-C₁₀-alkyl-cycloalkyl, cycloalkyl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkyl-cycloalkyl-C₁-C₁₀-alkyl. Any member of this groupoptionally is substituted with one or more substituents independentlyselected from the group consisting of halogen, C₁-C₆-alkyl, andhalo-C₁-C₆-alkyl.

In some preferred embodiments, E² is C₄-C₆-alkyl optionally substitutedwith one or more halogen.

In some preferred embodiments, E² is C₄-C₆-alkyl.

E⁵ is —OH or optionally-substituted carbocyclyl.

In some preferred embodiments, E⁵ is —OH or carbocyclyl wherein thecarbocyclyl optionally is substituted with one or more substituentsindependently selected from the group consisting of and halogen, —OH,—NO₂, —CN, keto, C₁-C₈-alkyl, halo-C₁-C₈-alkyl, C₁-C₈-alkoxy,halo-C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl, halogen-substitutedC₁-C₈-alkoxy-C₁-C₈-alkyl, —N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵,carbocyclyl, halocarbocyclyl, carbocyclyl-C₁-C₆-alkyl, andhalogen-substituted carbocyclyl-C₁-C₈-alkyl. The carbocyclyl alsooptionally is substituted with two C₁-C₈-alkyl or halo-C₁-C₈-alkylgroups on the same atom that form a C₅-C₆-Cycloalkyl orC₅-C₆-halocycloalkyl.

In some preferred embodiments, E⁵ is —OH or carbocyclyl wherein thecarbocyclyl optionally is substituted with one or more substituentsindependently selected from the group consisting of and halogen, —OH,—NO₂, —CN, keto, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy,halo-C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, halogen-substitutedC₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵,carbocyclyl, halocarbocyclyl, carbocyclyl-C₁-C₆-alkyl, andhalogen-substituted carbocyclyl-C₁-C₆-alkyl.

R¹ and R² are independently selected from the group consisting of —H andalkyl. The alkyl optionally is substituted. Neither R¹ nor R² forms aring structure with E⁵.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, and halo-C₁-C₈-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H and C₁-C₆-alkyl.

R⁵ and R⁶ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁵ and R⁶ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R⁷ is —H, C₁-C₈-alkyl, —O—R⁸, —N(R⁸)(R⁹), carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl. The C₁-C₈-alkyl, carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl may be substituted with one or more halogen,but more typically is preferably not substituted with halogen.

In some preferred embodiments, R⁷ is —H, C₁-C₆-alkyl, —O—R, —N(R₈)(R⁹),carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl. The C₁-C₆-alkyl,carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl may be substitutedwith one or more halogen, but more typically is preferably notsubstituted with halogen.

R⁸ and R⁹ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁸ and R⁹ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen. Such compounds include, for example:

In some preferred embodiments, E⁵ is optionally-substituted carbocyclyl,often preferably optionally-substituted aryl, and more preferablyoptionally-substituted phenyl. Such compounds include, for example:

In some preferred embodiments, E⁵ is —OH. Such compounds include, forexample:

Preferred Embodiment No. 9

In some embodiments of this invention, the compound has a structure toFormula X:

A¹, A², and A³ are as defined above for Formula I.

E¹ is —S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—, or—C(R¹)(R²)—.

E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, oralkylcycloalkyl. Any member of this group optionally is substituted.

In some preferred embodiments, E² is C₁-C₂₀-alkyl, cycloalkyl,C₁-C₁₀-alkylcycloalkyl, cycloalkyl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkylcycloalkyl-C₁-C₁₀-alkyl. Any member of this group optionallyis substituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆-alkyl, C₁-C₆-halo-alkyl.

In some preferred embodiments, E² is C₂-C₆-alkyl optionally substitutedwith one or more halogen.

In some preferred embodiments, E² is C₂-C₆-alkyl.

E⁴ is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally aresubstituted.

In some preferred embodiments, E⁴ is a bond, C₁-C₂₀-alkyl,halo-C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, or halo-C₂-C₂₀-alkenyl.

In some preferred embodiments, E⁴ is a bond, C₁-C₃-alkyl,halo-C₁-C₃-alkyl, C₂-C₃-alkenyl, or halo-C₂-C₃-alkenyl.

In some preferred embodiments, E⁴ is a bond, C₁-C₃-alkyl, orC₂-C₃-alkenyl.

E⁵ is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, orheterocyclyl. Any member of this group optionally is substituted.

In some preferred embodiments, E⁵ is C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl,C₂-C₂₀-alkynyl, C₁-C₂₀-alkoxy, C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl, carbocyclyl,or heterocyclyl. The C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, C₂-C₂₀-alkynyl,C₁-C₂₀-alkoxy, and C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl optionally are substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, and —CN. The carbocyclyl andheterocyclyl optionally are substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH, —NO₂,—CN, keto, C₁-C₈-alkyl, halo-C₁-C₈-alkyl, C₁-C₈-alkoxy,halo-C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl, halogen-substitutedC₁-C₈-alkoxy-C₁-C₈-alkyl, —N(R⁵)(R⁶), —C(O)(R¹), —S—R⁵, —S(O)₂—R⁵,carbocyclyl, halocarbocyclyl, carbocyclyl-C₁-C₈-alkyl, andhalogen-substituted carbocyclyl-C₁-C₈-alkyl.

In some preferred embodiments, E⁵ is C₁-C₈-alkyl, C₂-C₈-alkenyl,C₂-C₈-alkynyl, C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl, carbocyclyl, orheterocyclyl. The C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl,C₁-C₈-alkoxy, and C₁-C₈-alkoxy-C₁-C₈-alkyl optionally are substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, and —CN. The carbocyclyl andheterocyclyl optionally are substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH, —NO₂,—CN, keto, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy,halo-C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, halogen-substitutedC₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵,carbocyclyl, halocarbocyclyl, carbocyclyl-C₁-C₆-alkyl, andhalogen-substituted carbocyclyl-C₁-C₆-alkyl.

R¹ and R² are independently selected from the group consisting of —H andalkyl. The alkyl optionally is substituted. Neither R¹ nor R² forms aring structure with E², E⁴, or E⁵.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, and halo-C₁-C₈-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H and C₁-C₆-alkyl.

R⁵ and R⁶ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁵ and R⁶ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R⁷ is —H, C₁-C₆-alkyl, —O—R⁸, —N(R⁸)(R⁹), carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl. The C₁-C₈-alkyl, carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl may be substituted with one or more halogen,but more typically is preferably not substituted with halogen.

In some preferred embodiments, R⁷ is —H, C₁-C₆-alkyl, —O—R⁸, —N(R⁸)(R⁹),carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl. The C₁-C₆-alkyl,carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl may be substitutedwith one or more halogen, but more typically is preferably notsubstituted with halogen.

R⁸ and R⁹ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁸ and R⁹ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, E⁵ is C₁-C₈-alkyl, C₂-C₈-alkenyl,C₂-C₈-alkoxy, or C₁-C₈-alkoxy-C₁-C₈-alkyl. The C₁-C₈-alkyl,C₂-C₈-alkynyl, C₁-C₈-alkoxy, and C₁-C₈-alkoxy-C₁-C₈-alkyl optionally aresubstituted with one or more substituents independently selected fromthe group consisting of halogen, —OH, —NO₂, and —CN.

In some preferred embodiments, E⁵ is C₁-C₈-alkyl. Such compoundsinclude, for example:

Preferred Embodiment No. 10

In some embodiments of this invention, the compound has a structurecorresponding to Formula XI:

A¹, A², and A³ are as defined above for Formula I.

E² comprises at least 3 carbon atoms. E² is alkyl, cycloalkyl,alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member ofthis group optionally is substituted.

In some preferred embodiments, E² is C₃-C₂₀-alkyl, cycloalkyl,C₁-C₁₀-alkylcycloalkyl, cycloalkyl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkylcycloalkyl-C₁-C₁₀-alkyl. Any member of this group optionallyis substituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, E² is C₃-C₁₀-alkyl optionally issubstituted with one or more halogen.

In some preferred embodiments, E² is C₃-C₁₀-alkyl.

In some preferred embodiments, E² is C₃-C₅-alkyl.

E⁵ is —H, alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl,carbocyclylalkoxyalkyl, heterocyclyl, heterocyclylalkyl, orheterocyclylalkoxyalkyl. The alkyl, alkenyl, alkynyl, and alkoxyalkyloptionally are substituted with one or more substituents independentlyselected from the group consisting of halogen, —OH, —NO₂, and —CN. Thecarbocyclyl, carbocyclylalkoxyalkyl, heterocyclyl, heterocyclylalkyl,and heterocyclylalkoxyalkyl optionally are substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO₂, —CN, alkyl, haloalkyl, alkoxy, haloalkoxy,alkoxyalkyl, halogen-substituted alkoxyalkyl, —N(R³)(R⁴), —C(O)(R⁵),—S—R³, —S(O)₂—R³, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, andhalogen-substituted carbocyclylalkyl.

In some preferred embodiments, E⁵ is —H, C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl,C₂-C₂₀-alkynyl, C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl, carbocyclyl,carbocyclyl-C₁-C₁₀-alkoxy-C₁-C₁₀-alkyl, heterocyclyl,heterocyclyl-C₁-C₁₀-alkyl, or heterocyclyl-C₁-C₁₀-alkoxy-C₁-C₁₀-alkyl.The C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, C₂-C₂₀-alkynyl, andC₁-C₂₀-alkoxy-C₁-C₂₀-alkyl optionally are substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO₂, and —CN. The carbocyclyl,carbocyclyl-C₁-C₁₀-alkoxy-C₁-C₁₀-alkyl, heterocyclyl,heterocyclyl-C₁-C₁₀-alkyl, and heterocyclyl-C₁-C₁₀-alkoxy-C₁-C₁₀-alkyloptionally are substituted with one or more substituents independentlyselected from the group consisting of halogen, —OH, —NO₂, —CN, keto,C₁-C₈-alkyl, halo-C₁-C₈-alkyl, C₁-C₈-alkoxy, halo-C₁-C₈-alkoxy,C₁-C₈-alkoxy-C₁-C₈-alkyl, halogen-substituted C₁-C₈-alkoxy-C₁-C₈-alkyl,—N(R³)(R⁴), —C(O)(R⁵), —S—R³, —S(O)₂—R³, carbocyclyl, halocarbocyclyl,carbocyclyl-C₁-C₈-alkyl, and halogen-substitutedcarbocyclyl-C₁-C₈-alkyl.

In some preferred embodiments, E⁵ is —H, C₁-C₈-alkyl, C₂-C₈-alkenyl,C₂-C₈-alkynyl, C₁-C₈-alkoxy-C₁-C₈-alkyl, carbocyclyl,carbocyclyl-C₁-C₈-alkoxy-C₁-C₈-alkyl, heterocyclyl,heterocyclyl-C₁-C₈-alkyl, or heterocyclyl-C₁-C₈-alkoxy-C₁-C₈-alkyl. TheC₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, and C₁-C₈-alkoxy-C₁-C₈-alkyloptionally are substituted with one or more substituents independentlyselected from the group consisting of halogen, —OH, —NO₂, and —CN. Thecarbocyclyl, carbocyclyl-C₁-C₈-alkoxy-C₁-C₈-alkyl, heterocyclyl,heterocyclyl-C₁-C₈-alkyl, and heterocyclyl-C₁-C₈-alkoxy-C₁-C₈-alkyloptionally are substituted with one or more substituents independentlyselected from the group consisting of halogen, —OH, —NO₂, —CN, keto,C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl,—N(R³)(R⁴), —C(O)(R⁵), —S—R³, —S(O)₂—R³, carbocyclyl, halocarbocyclyl,carbocyclyl-C₁-C₆-alkyl, and halogen-substitutedcarbocyclyl-C₁-C₆-alkyl.

R¹ and R² are independently selected from the group consisting of —H,alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, andheterocyclylalkyl. Except where the member is —H, any member of thisgroup may be substituted with one or more halogen, but more typically ispreferably not substituted with halogen.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, carbocyclyl,carbocyclyl-C₁-C₈-alkyl, heterocyclyl, and heterocyclyl-C₁-C₈-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R³ is —H, alkyl, —OR⁴, —N(R⁴)(R⁵), carbocyclylalkyl, orheterocyclylalkyl. The alkyl, carbocyclylalkyl, or heterocyclylalkyl maybe substituted with one or more halogen, but more typically ispreferably not substituted with halogen.

In some preferred embodiments, R³ is —H, C₁-C₈-alkyl, —O—R⁴, —N(R⁴)(R⁵),carbocyclyl-C₁-C₈-alkyl, or heterocyclyl-C₁-C₈-alkyl. The C₁-C₈-alkyl,carbocyclyl-C₁-C₈-alkyl, or heterocyclyl-C₁-C₈-alkyl may be substitutedwith one or more halogen, but more typically is preferably notsubstituted with halogen.

In some preferred embodiments, R³ is —H, C₁-C₆-alkyl, —O—R⁴, —N(R⁴)(R⁵),carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl. The C₁-C₆-alkyl,carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl may be substitutedwith one or more halogen, but more typically is preferably notsubstituted with halogen.

R⁴ and R⁵ are independently selected from the group consisting of —H,alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, andheterocyclylalkyl. Except where the member is —H, any member of thisgroup may be substituted with one or more halogen, but more typically ispreferably not substituted with halogen.

In some preferred embodiments, R⁴ and R⁵ are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, carbocyclyl,carbocyclyl-C₁-C₈-alkyl, heterocyclyl, and heterocyclyl-C₁-C₈-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, R⁴ and R⁵ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, E⁵ is —H, C₁-C₈-alkyl, C₂-C₈-alkenyl,C₂-C₈-alkynyl, or C₁-C₈-alkoxy-C₁-C₈-alkyl. The C₁-C₈-alkyl,C₂-C₈-alkenyl, C₂-C₈-alkynyl, and C₁-C₈-alkoxy-C₁-C₈-alkyl optionallyare substituted with one or more substituents independently selectedfrom the group consisting of halogen, —OH, —NO₂, and —CN. Such compoundsinclude, for example:

In some preferred embodiments, E⁵ is carbocyclyl,carbocyclyl-C₁-C₈-alkoxy-C₁-C₈-alkyl, heterocyclyl,heterocyclyl-C₁-C₈-alkyl, or heterocyclyl-C₁-C₈-alkoxy-C₁-C₈-alkyl. thecarbocyclyl, carbocyclyl-C₁-C₈-alkoxy-C₁-C₈-alkyl, heterocyclyl,heterocyclyl-C₁-C₈-alkyl, and heterocyclyl-C₁-C₈-alkoxy-C₁-C₈-alkyloptionally are substituted with one or more substituents independentlyselected from the group consisting of halogen, —OH, —NO₂, —CN, keto,C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl,—N(R³)(R⁴), —C(O)(R⁵), —S—R³, —S(O)₂—R³, carbocyclyl, halocarbocyclyl,carbocyclyl-C₁-C₆-alkyl, and halogen-substitutedcarbocyclyl-C₁-C₆-alkyl.

In some preferred embodiments, E⁵ is optionally-substituted carbocyclyl.

In some preferred embodiments, E⁵ is optionally-substituted phenyl. Suchcompounds include, for example:

In some preferred embodiments, E⁵ is optionally-substitutednaphthalenyl. Such compounds include, for example:

In some preferred embodiments, E⁵ is heterocyclyl orheterocyclyl-C₁-C₈-alkyl. Such compounds include, for example:

Preferred Embodiment No. 11

In some embodiments of this invention, the compound has a structure toFormula XII:

A¹, A², and A³ are as defined above for Formula I.

E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkyl. Anymember of this group optionally is substituted. An atom in E² bound toan atom in E⁵ to form a ring.

In some preferred embodiments, E² is C₁-C₂₀-alkyl, cycloalkyl,C₁-C₁₀-alkylcycloalkyl, cycloalkyl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkylcycloalkyl-C₁-C₁₀-alkyl. Any member of this group optionallyis substituted with one or more substituents selected from the groupconsisting of halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl.

In some preferred embodiments, E² is C₂-C₆-alkyl optionally substitutedwith one or more halogen.

In some preferred embodiments, E² is C₂-C₆-alkyl.

E⁴ is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally aresubstituted.

In some preferred embodiments, E⁴ is a bond, C₁-C₂₀-alkyl,halo-C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, or halo-C₂-C₂alkenyl.

In some preferred embodiments, E⁴ is a bond, C₁-C₃-alkyl,halo-C₁-C₃-alkyl, C₂-C₃-alkenyl, or halo-C₂-C₃-alkenyl.

In some preferred embodiments, E⁴ is a bond, C₁-C₃-alkyl, orC₂-C₃-alkenyl.

In some preferred embodiments, E⁴ is methyl.

In some preferred embodiments, E⁴ is a bond.

E⁵ is:

-   -   an optionally-substituted radical selected from the group        consisting of alkenyl, alkynyl, alkoxy, alkoxyalkyl, fused-ring        carbocyclyl, and heterocyclyl; or    -   single-ring carbocyclyl substituted with one or more        substituents independently selected from the group consisting of        —OH, —NO₂, —CN, —N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵,        carbocyclyl, halocarbocyclyl, carbocyclylalkyl,        halogen-substituted carbocyclylalkyl, heterocyclyl,        haloheterocyclyl, heterocyclylalkyl, and halogen-substituted        heterocyclylalkyl; or    -   single-ring carbocyclyl having multiple substitutions.

In some preferred embodiments, E⁵ is C₂-C₂₀-alkenyl, C₂-C₂₀-alkynyl,C₁-C₂₀-alkoxy, C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl, heterocyclyl, single-ringcarbocyclyl, or fused-ring carbocyclyl. The C₂-C₂₀-alkenyl,C₂-C₂₀-alkynyl, C₁-C₂₀-alkoxy, and C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl optionallyare substituted with one or more substituents independently selectedfrom the group consisting of halogen, —OH, —NO₂, and —CN. Theheterocyclyl and fused-ring carbocyclyl optionally are substituted withone or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, —CN, C₁-C₆-alkyl, halo-C₁-C₈-alkyl,C₁-C₈-alkoxy, halo-C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl,halogen-substituted C₁-C₈-alkoxy-C₁-C₈-alkyl, —N(R⁵)(R⁶), —C(O)(R⁷),—S—R⁵, —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl, carbocyclyl-C₁-C₆-alkyl,halogen-substituted carbocyclyl-C₁-C₈-alkyl, heterocyclyl,haloheterocyclyl, heterocyclyl-C₁-C₈-alkyl, and halogen-substitutedheterocyclyl-C₁-C₈-alkyl. The single-ring carbocyclyl is either:

-   -   substituted with one or more substituents independently selected        from the group consisting of —OH, —NO₂, —CN, —N(R⁵)(R⁶),        —C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl,        carbocyclyl-C₁-C₈-alkyl, halogen-substituted        carbocyclyl-C₁-C₈-alkyl, heterocyclyl, haloheterocyclyl,        heterocyclyl-C₁-C₈-alkyl, and halogen-substituted        heterocyclyl-C₁-C₈-alkyl, or    -   substituted with 2 or more substituents independently selected        from the group consisting of halogen, —OH, —NO₂, —CN,        C₁-C₈-alkyl, halo-C₁-C₈-alkyl, C₁-C₈-alkoxy, halo-C₁-C₈-alkoxy,        C₁-C₈-alkoxy-C₁-C₈-alkyl, halogen-substituted        C₁-C₈-alkoxy-C₁-C₈-alkyl, —N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵,        —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl,        carbocyclyl-C₁-C₈-alkyl, halogen-substituted        carbocyclyl-C₁-C₈-alkyl, heterocyclyl, haloheterocyclyl,        heterocyclyl-C₁-C₈-alkyl, and halogen-substituted        heterocyclyl-C₁-C₈-alkyl.

In some preferred embodiments, E⁵ is C₂-C₈-alkenyl, C₂-C₈-alkynyl,C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₂-C₈-alkyl, heterocyclyl, single-ringcarbocyclyl, or fused-ring carbocyclyl. The C₂-C₈-alkenyl,C₂-C₈-alkynyl, C₁-C₈-alkoxy, and C₁-C₈-alkoxy-C₁-C₈-alkyl optionally aresubstituted with one or more substituents independently selected fromthe group consisting of halogen, —OH, —NO₂, and —CN. The heterocyclyland fused-ring carbocyclyl optionally are substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO₂, —CN, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy,halo-C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, halogen-substitutedC₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵,carbocyclyl, halocarbocyclyl, carbocyclyl-C₁-C₆-alkyl,halogen-substituted carbocyclyl-C₁-C₆-alkyl, heterocyclyl,haloheterocyclyl, heterocyclyl-C₁-C₆-alkyl, and halogen-substitutedheterocyclyl-C₁-C₆-alkyl. The single-ring carbocyclyl is either:

-   -   substituted with one or more substituents independently selected        from the group consisting of —OH, —NO₂, —CN, —N(R⁵)(R⁶),        —C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl,        carbocyclyl-C₁-C₆-alkyl, halogen-substituted        carbocyclyl-C₁-C₆-alkyl, heterocyclyl, haloheterocyclyl,        heterocyclyl-C₁-C₆-alkyl, and halogen-substituted        heterocyclyl-C₁-C₆-alkyl; or    -   substituted with 2 or more substituents independently selected        from the group consisting of halogen, —OH, —NO₂, —CN,        C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy,        C₁-C₆-alkoxy-C₁-C₆-alkyl, halogen-substituted        C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵,        —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl,        carbocyclyl-C₁-C₆-alkyl, halogen-substituted        carbocyclyl-C₁-C₆-alkyl, heterocyclyl, haloheterocyclyl,        heterocyclyl-C₁-C₆-alkyl, and halogen-substituted        heterocyclyl-C₁-C₆-alkyl.

R¹ and R² are independently selected from the group consisting of —H,alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, andheterocyclylalkyl. Except where the member is —H, any member of thisgroup may be substituted with one or more halogen, but more typically ispreferably not substituted with halogen.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₈-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R³ is —H, alkyl, —O—R⁴, —N(R⁴)(R⁵), carbocyclylalkyl, orheterocyclylalkyl. The alkyl, carbocyclylalkyl, or heterocyclylalkyl maybe substituted with one or more halogen, but more typically ispreferably not substituted with halogen.

In some preferred embodiments, R³ is —H, C₁-C₈-alkyl, —O—R⁴, —N(R⁴)(R⁵),carbocyclyl-C₁-C₈-alkyl, or heterocyclyl-C₁-C₈-alkyl. The C₁-C₈-alkyl,carbocyclyl-C₁-C₈-alkyl, or heterocyclyl-C₁-C₈-alkyl may be substitutedwith one or more halogen, but more typically is preferably notsubstituted with halogen.

In some preferred embodiments, R³ is —H, C₁-C₆-alkyl, —O—R⁴, —N(⁴)(R⁵),carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl. The C₁-C₈-alkyl,carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl may be substitutedwith one or more halogen, but more typically is preferably notsubstituted with halogen.

R⁴ and R⁵ are independently selected from the group consisting of —H,alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, andheterocyclylalkyl. Except where the member is —H, any member of thisgroup may be substituted with one or more halogen, but more typically ispreferably not substituted with halogen.

In some preferred embodiments, R⁴ and R⁵ are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, carbocyclyl,carbocyclyl-C₁-C₈-alkyl, heterocyclyl, and heterocyclyl-C₁-C₈-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, R⁴ and R⁵ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, E² is bound to an atom of E⁵ to form aring. Such compounds include, for example:

In some preferred embodiments, E² is not bound to an atom of E⁵ to forma ring.

In some such preferred embodiments, E⁵ is a single-ring carbocyclyl(preferably phenyl) substituted with one or more substituentsindependently selected from the group consisting of —OH, —NO₂, —CN,—N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl,carbocyclyl-C₁-C₆-alkyl, halogen-substituted carbocyclyl-C₁-C₆-alkyl,heterocyclyl, haloheterocyclyl, heterocyclyl-C₁-C₆-alkyl, andhalogen-substituted heterocyclyl-C₁-C₆-alkyl. Such compounds include,for example:

In some preferred embodiments, E⁵ is single-ring carbocyclyl (preferablyphenyl) substituted with 2 or more substituents independently selectedfrom the group consisting of halogen, —OH, —NO₂, —CN, C₁-C₆-alkyl,halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, —N(R⁵)(R⁶),—C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl,carbocyclyl-C₁-C₆-alkyl, halogen-substituted carbocyclyl-C₁-C₆-alkyl,heterocyclyl, haloheterocyclyl, heterocyclyl-C₁-C₆-alkyl, andhalogen-substituted heterocyclyl-C₁-C₆-alkyl. Such compounds include,for example:

In some preferred embodiments, E⁵ is heterocyclyl optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, —CN, C₁-C₆-alkyl, halo-C₁-C₆-alkyl,C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R⁵)(R⁶), —C(O)(R⁷),—S—R⁵, —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl, carbocyclyl-C₁-C₆-alkyl,halogen-substituted carbocyclyl-C₁-C₆-alkyl, heterocyclyl,haloheterocyclyl, heterocyclyl-C₁-C-alkyl, and halogen-substitutedheterocyclyl-C₁-C₆-alkyl. Such compounds include, for example:

Preferred Embodiment No. 12

In some embodiments of this invention, the compound has a structurecorresponding to Formula XIII:

A¹, A², and A³ are as defined above for Formula I.

E¹ is —S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—, or—C(R¹)(R²)—.

E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, oralkylcycloalkylalkyl. Any member of this group optionally issubstituted.

In some preferred embodiments, E² is C₁-C₂₀-alkyl, cycloalkyl,C₁-C₁₀-alkylcycloalkyl, cycloalkyl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkylcycloalkyl-C₁-C₁₀-alkyl. Any member of this group optionallyis substituted with one or more substituents selected from the groupconsisting of halogen, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, E² is C₁-C₆-alkyl, cycloalkyl,C₁-C₆-alkylcycloalkyl, cycloalkyl-C₁-C₆-alkyl, orC₁-C₆-alkylcycloalkyl-C₁-C₆-alkyl. Any member of this group optionallyis substituted with one or more halogen, although such substituenttypically is preferably not substituted with halogen.

E⁴ is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally aresubstituted.

In some preferred embodiments, E⁴ is a bond, C₁-C₂₀-alkyl,halo-C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, or halo-C₂-C₂₀-alkenyl.

In some preferred embodiments, E⁴ is a bond, C₁-C₃-alkyl,halo-C₁-C₃-alkyl, C₂-C₃-alkenyl, or halo-C₂-C₃-alkenyl.

In some preferred embodiments, E⁴ is a bond, C₁-C₃-alkyl, orC₂-C₃-alkenyl.

E⁵ is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, orheterocyclyl. Any member of this group optionally is substituted.

In some preferred embodiments, E⁵ is C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl,C₂-C₂₀-alkynyl, C₁-C₂₀-alkoxy, C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl, carbocyclyl,or heterocyclyl. The C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, C₂-C₂₀-alkynyl,C₁-C₂₀-alkoxy, and C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl optionally are substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, and —CN. The carbocyclyl andheterocyclyl optionally are substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH, —NO₂,—CN, C₁-C₈-alkyl, halo-C₁-C₈-alkyl, C₁-C₈-alkoxy, halo-C₁-C₈-alkoxy,—N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl,carbocyclyl-C₁-C₈-alkyl, and halogen-substitutedcarbocyclyl-C₁-C₈-alkyl.

In some preferred embodiments, E⁵ is C₁-C₈-alkyl, C₂-C₈-alkenyl,C₂-C₈-alkynyl, C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl, carbocyclyl, orheterocyclyl. The C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl,C₁-C₈-alkoxy, and C₁-C₈-alkoxy-C₁-C₈-alkyl optionally are substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, and —CN. The carbocyclyl andheterocyclyl optionally are substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH, —NO₂,—CN, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy,—N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl,carbocyclyl-C₁-C₆-alkyl, and halogen-substitutedcarbocyclyl-C₁-C₆-alkyl.

R¹ and R² are independently selected from the group consisting of —H andalkyl. The alkyl optionally is substituted. Neither R¹ nor R² forms aring structure with E², E⁴, or E⁵.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, and halo-C₁-C₈-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H and C₁-C₆-alkyl.

R⁵ and R⁶ are independently selected from the group consisting of —H,C₁-C₆-alkyl, carbocyclyl, carbocyclyl-C₁-C₆-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁵ and R⁶ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R⁷ is —H, C₁-C₆-alkyl, —O—R⁸, —N(R⁸)(R⁹), carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl. The C₁-C₈-alkyl, carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl may be substituted with one or more halogen,but more typically is preferably not substituted with halogen.

In some preferred embodiments, R⁷ is —H, C₁-C₆-alkyl, —O—R⁸, —N(R⁸)(R⁹),carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl. The C₁-C₆-alkyl,carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl may be substitutedwith one or more halogen, but more typically is preferably notsubstituted with halogen.

R⁸ and R⁹ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁸ and R⁹ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

Preferred Embodiment No. 13

In some embodiments of this invention, the compound has a structurecorresponding to Formula XIV:

A¹, A², and A³ are as defined above for Formula I.

E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, oralkylcycloalkylalkyl. Any member of this group optionally issubstituted.

In some preferred embodiments, E² is C₁-C₂₀-alkyl, cycloalkyl,C₁-C₁₀-alkylcycloalkyl, cycloalkyl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkylcycloalkyl-C₁-C₁₀-alkyl. Any member of this group optionallyis substituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, E² is C₁-C₆-alkyl optionally substitutedwith one or more halogen.

In some preferred embodiments, E² is C₁-C₆-alkyl.

E⁴ is alkyl or alkenyl. The alkyl and alkenyl optionally aresubstituted.

In some preferred embodiments, E⁴ is C₁-C₂₀-alkyl, halo-C₁-C₂₀-alkyl,C₂-C₂₀-alkenyl, or halo-C₂-C₂₀-alkenyl.

In some preferred embodiments, E⁴ is C₁-C₃-alkyl, halo-C₁-C₃-alkyl,C₂-C₃-alkenyl, or halo-C₂-C₃-alkenyl.

In some preferred embodiments, E⁴ is C₁-C₃-alkyl or C₂-C₃-alkenyl.

E⁵ is —H, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, or heterocyclyl.Any member of this group optionally is substituted.

In some preferred embodiments, E⁵ is —H, C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl,C₂-C₂₀-alkynyl, C₁-C₂₀-alkoxy, carbocyclyl, or heterocyclyl. TheC₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, C₂-C₂₀-alkynyl, and C₁-C₂₀-alkoxyoptionally are substituted with one or more substituents independentlyselected from the group consisting of halogen, —OH, —NO₂, and —CN. Thecarbocyclyl and heterocyclyl optionally are substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO₂, —CN, C₁-C₈-alkyl, halo-C₁-C₈-alkyl, C₁-C₈-alkoxy,halo-C₁-C₈-alkoxy, —N(R³)(R⁴), —C(O)(R⁵), —S—R³, —S(O)₂—R³, carbocyclyl,halocarbocyclyl, carbocyclyl-C₁-C₈-alkyl, and halogen-substitutedcarbocyclyl-C₁-C₈-alkyl.

In some preferred embodiments, E⁵ is —H, C₁-C₈-alkyl, C₂-C₈-alkenyl,C₂-C₈-alkynyl, C₁-C₈-alkoxy, carbocyclyl, or heterocyclyl. TheC₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, and C₁-C₈-alkoxy optionallyare substituted with one or more substituents independently selectedfrom the group consisting of halogen, —OH, —NO₂, and —CN. Thecarbocyclyl and heterocyclyl optionally are substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO₂, —CN, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy,halo-C₁-C₆-alkoxy, —N(R³)(R⁴), —C(O)(R⁵), —S—R³, —S(O)₂—R³, carbocyclyl,halocarbocyclyl, carbocyclyl-C₁-C₆-alkyl, and halogen-substitutedcarbocyclyl-C₁-C₆-alkyl.

R³ and R⁴ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R³ and R⁴ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R⁵ is —H, C₁-C₈-alkyl, —O—R⁶, —N(R⁶)(R⁷), carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl. The C₁-C₈-alkyl, carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl may be substituted with one or more halogen,but more typically is preferably not substituted with halogen.

In some preferred embodiments, R⁵ is —H, C₁-C₆-alkyl, —O—R⁶, —N(R⁶)(R⁷),carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl. The C₁-C₆-alkyl,carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl may be substitutedwith one or more halogen, but more typically is preferably notsubstituted with halogen.

R⁶ and R⁷ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁶ and R⁷ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, E⁵ is —H, C₁-C₈-alkyl, C₂-C₈-alkenyl,C₂-C₈-alkynyl, or C₁-C₈-alkoxy. The C₁-C₈-alkyl, C₂-C₈-alkenyl,C₂-C₈-alkynyl, and C₁-C₈-alkoxy optionally are substituted with one ormore substituents independently selected from the group consisting ofhalogen, —OH, —NO₂, and —CN. In one such embodiment, E⁵ is C₁-C₈-alkyloptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, —OH, —NO₂, and —CN. Suchcompounds include, for example:

In some preferred embodiments, E⁵ is optionally-substituted carbocyclyland optionally-substituted heterocyclyl.

In some preferred embodiments, E⁵ is optionally-substituted aryl, oftenpreferably optionally-substituted phenyl. Such compounds include, forexample:

Preferred Embodiment No. 14

In some embodiments of this invention, the compound has a structurecorresponding to Formula XV:

A¹, A², and A³ are as defined above for Formula I.

E² comprises less than 5 carbon atoms. E² is alkyl, cycloalkyl,alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member ofthis group optionally is substituted, but preferably is not substituted.

E⁵ is alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl, orheterocyclyl. Any member of this group optionally is substituted.

In some preferred embodiments, E⁵ is C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl,C₂-C₂₀-alkynyl, C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl, carbocyclyl, orheterocyclyl. The C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, C₂-C₂₀-alkynyl, andC₁-C₂₀-alkoxy-C₁-C₂₀-alkyl optionally are substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO₂, and —CN. The carbocyclyl and heterocyclyl optionallyare substituted with one or more substituents independently selectedfrom the group consisting of halogen, —OH, —NO₂, —CN, keto, C₁-C₈-alkyl,halo-C₁-C₈-alkyl, C₁-C₈-alkoxy, halo-C₁-C₈-alkoxy,C₁-C₈-alkoxy-C₁-C₈-alkyl, halogen-substituted C₁-C₈-alkoxy-C₁-C₈-alkyl,—N(R³)(R⁴), —C(O)(R⁵), —S—R³, —S(O)₂—R³, carbocyclyl, halocarbocyclyl,carbocyclyl-C₁-C₈-alkyl, halogen-substituted carbocyclyl-C₁-C₈-alkyl,C₁-C₈-alkylcarbocyclyloxy, and halogen-substitutedC₁-C₈-alkylcarbocyclyloxy.

In some preferred embodiments, E⁵ is C₁-C₈-alkyl, C₁-C₈-alkenyl,C₂-C₈-alkynyl, C₁-C₈-alkoxy-C₁-C₈-alkyl, carbocyclyl, or heterocyclyl.The C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, andC₁-C₈-alkoxy-C₁-C₈-alkyl optionally are substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO₂, and —CN. The carbocyclyl and heterocyclyl optionallyare substituted with one or more substituents independently selectedfrom the group consisting of halogen, —OH, —NO₂, —CN, keto, C₁-C₆-alkyl,halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl,—N(R³)(R⁴), —C(O)(R⁵), —S—R³, —S(O)₂—R³, carbocyclyl, halocarbocyclyl,carbocyclyl-C₁-C₆-alkyl, halogen-substituted carbocyclyl-C₁-C₆-alkyl,C₁-C₆-alkylcarbocyclyloxy, and halogen-substitutedC₁-C₆-alkylcarbocyclyloxy.

R³ and R⁴ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R³ and R⁴ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R⁵ is —H, C₁-C₈-alkyl, —O—R⁶, —N(R⁶)(R⁷), carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl. The C₁-C₈-alkyl, carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl may be substituted with one or more halogen,but more typically is preferably not substituted with halogen.

In some preferred embodiments, R⁵ is —H, C₁-C₆-alkyl, —O—R⁶, —N(R⁶)(R⁷),carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl. The C₁-C₆-alkyl,carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl may be substitutedwith one or more halogen, but more typically is preferably notsubstituted with halogen.

R⁶ and R⁷ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁶ and R⁷ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, E⁵ is C₁-C₈-alkyl, C₂-C₈-alkenyl,C₂-C₈-alkynyl, or C₁-C₈-alkoxy-C₁-C₈-alkyl. The C₁-C₈-alkyl,C₂-C₈-alkenyl, C₂-C₈-alkynyl, and C₁-C₈-alkoxy-C₁-C₈-alkyl optionallyare substituted with one or more substituents independently selectedfrom the group consisting of halogen, —OH, —NO₂, and —CN.

In some preferred embodiments, E⁵ is optionally-substituted carbocyclyl.

In some preferred embodiments, E⁵ is optionally-substitutedC₅-C₆-Cycloalkyl. Such compounds include, for example:

In some preferred embodiments, E⁵ is optionally-substituted phenyl. Suchcompounds include, for example:

In some preferred embodiments, E⁵ is optionally-substitutedheterocyclyl.

In some preferred embodiments, E⁵ is optionally-substituted heterocyclylselected from the group consisting of piperidinyl, morpholinyl, andtetrahydroisoquinolinyl. Such compounds include, for example:

Preferred Embodiment No. 15

In some embodiments of this invention, the compound has a structurecorresponding to Formula XVI:

A¹, A², and A³ are as defined above for Formula I.

E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, oralkylcycloalkylalkyl. Any member of this group optionally issubstituted.

In some preferred embodiments, E² is C₁-C₂₀-alkyl, cycloalkyl,C₁-C₁₀-alkylcycloalkyl, cycloalkyl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkylcycloalkyl-C₁-C₁₀-alkyl. Any member of this group optionallyis substituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl.

In some preferred embodiments, E² is C₁-C₆-alkyl optionally substitutedwith one or more halogen.

In some preferred embodiments, E² is C₁-C₆-alkyl.

E⁵ is alkyl, alkenyl, alkynyl, alkoxyalkyl, saturated carbocyclyl,partially saturated carbocyclyl, or heterocyclyl. Any member of thisgroup optionally is substituted.

In some preferred embodiments, E⁵ is C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl,C₂-C₂₀-alkynyl, C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl, saturated carbocyclyl,partially saturated carbocyclyl, or heterocyclyl. The C₁-C₂₀-alkyl,C₂-C₂₀-alkenyl, C₂-C₂₀-alkynyl, and C₁-C₂₀-alkoxy-C₁-C₂₀-alkyloptionally are substituted with one or more substituents independentlyselected from the group consisting of halogen, —OH, —NO₂, and —CN. Thesaturated carbocyclyl, partially saturated carbocyclyl, and heterocyclyloptionally are substituted with one or more substituents independentlyselected from the group consisting of halogen, —OH, —NO₂, —CN,C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₈-alkoxy, halo-C₁-C₈-alkoxy,C₁-C₈-alkoxy-C₁-C₈-alkyl, halogen-substituted C₁-C₈-alkoxy-C₁-C₈-alkyl,—N(R³)(R⁴), —C(O)(R⁵), —S—R³, —S(O)₂—R³, carbocyclyl, halocarbocyclyl,carbocyclyl-C₁-C₆-alkyl, halogen-substituted carbocyclyl-C₁-C₈-alkyl,C₁-C₈-alkylcarbocyclyloxy, and halogen-substitutedC₁-C₈-alkylcarbocyclyloxy.

In some preferred embodiments, E⁵ is C₁-C₈-alkyl, C₂-C₈-alkenyl,C₂-C₈-alkynyl, C₁-C₈-alkoxy-C₁-C₈-alkyl, saturated carbocyclyl,partially saturated carbocyclyl, or heterocyclyl. The C₁-C₈-alkyl,C₂-C₈-alkenyl, C₂-C₈-alkynyl, and C₁-C₈-alkoxy-C₁-C₈-alkyl optionallyare substituted with one or more substituents independently selectedfrom the group consisting of halogen, —OH, —NO₂, and —CN. The saturatedcarbocyclyl, partially saturated carbocyclyl, and heterocyclyloptionally are substituted with one or more substituents independentlyselected from the group consisting of halogen, —OH, —NO₂, —CN,C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl,—N(R³)(R⁴), —C(O)(R⁵), —S—R³, —S(O)₂—R³, carbocyclyl, halocarbocyclyl,carbocyclyl-C₁-C₆-alkyl, halogen-substituted carbocyclyl-C₁-C₆-alkyl,C₁-C₆-alkylcarbocyclyloxy, and halogen-substitutedC₁-C₆-alkylcarbocyclyloxy.

R³ and R⁴ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R³ and R⁴ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R⁵ is s —H, C₁-C₈-alkyl, —O—R⁶, —N(R⁶)(R⁷), carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl. The C₁-C₈-alkyl, carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl may be substituted with one or more halogen,but more typically is preferably not substituted with halogen.

In some preferred embodiments, R⁵ is —H, C₁-C₆-alkyl, —O—R⁶, —N(R⁶)(R⁷),carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl. The C₁-C₆-alkyl,carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl may be substitutedwith one or more halogen, but more typically is preferably notsubstituted with halogen.

R⁶ and R⁷ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁶ and R⁷ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, E⁵ is C₁-C₈-alkyl, C₂-C₈-alkenyl,C₂-C₈-alkynyl, or C₁-C₈-alkoxy-C₁-C₈-alkyl. The C₁-C₈-alkyl,C₂-C₈-alkenyl, C₂-C₈-alkynyl, and C₁-C₈-alkoxy-C₁-C₈₋alkyl optionallyare substituted with one or more substituents independently selectedfrom the group consisting of halogen, —OH, —NO₂, and —CN.

In some preferred embodiments, E⁵ is optionally-substituted,partially-saturated carbocyclyl.

In some preferred embodiments, E⁵ is optionally-substituted, saturatedcarbocyclyl (preferably optionally-substituted C₅-C₆-cycloalkyl). Suchcompounds include, for example:

In some preferred embodiments, E⁵ is optionally-substitutedheterocyclyl. Such compounds include, for example:

Preferred Embodiment No. 16

In some embodiments of this invention, the compound has a structurecorresponding to Formula XVII:

A¹, A², and A³ are as defined above for Formula I.

E¹ is —S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—, or—C(R¹)(R¹)—.

E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, oralkylcycloalkylalkyl. Any member of this group optionally issubstituted.

In some preferred embodiments, E² is C₁-C₂₀-alkyl, cycloalkyl,C₁-C₁₀-alkylcycloalkyl, cycloalkyl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkylcycloalkyl-C₁-C₁₀-alkyl. Any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, E² is C₁-C₆-alkyl optionally substitutedwith one or more halogen.

In some preferred embodiments, E² is C₁-C₆-alkyl.

E⁴ is a bond, alkyl, or alkenyl, The alkyl and alkenyl optionally aresubstituted.

In some preferred embodiments, E⁴ is a bond, C₁-C₂₀-alkyl,halo-C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, or halo-C₂-C₂₀-alkenyl.

In some preferred embodiments, E⁴ is a bond, C₁-C₃-alkyl,halo-C₁-C₃-alkyl, C₂-C₃-alkenyl, or halo-C₂-C₃-alkenyl.

In some preferred embodiments, E⁴ is a bond, C₁-C₃-alkyl, orC₂-C₃-alkenyl.

E⁵ is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, orheterocyclyl. Any member of this group optionally is substituted.

In some preferred embodiments, E⁵ is C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl,C₂-C₂₀-alkynyl, C₁-C₂₀-alkoxy, C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl, carbocyclyl,or heterocyclyl. The C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, C₂-C₂₀-alkynyl,C₁-C₂₀-alkoxy, and C₁-C₂₀-alkoxy-C₁-C₂₀-alkyl optionally are substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, and —CN. The carbocyclyl andheterocyclyl optionally are substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH, —NO₂,—CN, C₁-C₈-alkyl, halo-C₁-C₈-alkyl, C₁-C₈-alkoxy, halo-C₁-C₈-alkoxy,C₁-C₈-alkoxy-C₁-C₈-alkyl, halogen-substituted C₁-C₈-alkoxy-C₁-C₈-alkyl,—N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl,carbocyclyl-C₁-C₈-alkyl, and halogen-substitutedcarbocyclyl-C₁-C₈-alkyl.

In some preferred embodiments, E⁵ is C₁-C₈-alkyl, C₂-C₈-alkenyl,C₂-C₈-alkynyl, C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl, carbocyclyl, orheterocyclyl. The C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl,C₁-C₈-alkoxy, and C₁-C₈-alkoxy-C₁-C₈-alkyl optionally are substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, and —CN. The carbocyclyl andheterocyclyl optionally are substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH, —NO₂,—CN, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl,—N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl,carbocyclyl-C₁-C₆-alkyl, and halogen-substitutedcarbocyclyl-C₁-C₆-alkyl.

R¹ and R² are independently selected from the group consisting of —H andalkyl. The alkyl optionally is substituted. Neither R¹ nor R² forms aring structure with E², E⁴, or E⁵.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, and halo-C₁-C₈-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H and C₁-C₆-alkyl.

R⁵ and R⁶ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁵ and R⁶ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R⁷ is —H, C₁-C₆-alkyl, —O—R⁸, —N(R⁸)(R⁹), carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl. The C₁-C₈-alkyl, carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl may be substituted with one or more halogen,but more typically is preferably not substituted with halogen.

In some preferred embodiments, R⁷ is —H, C₁-C₆-alkyl, —O—R⁸, —N(R⁸)(R⁹),carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl. The C₁-C₆-alkyl,carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl may be substitutedwith one or more halogen, but more typically is preferably notsubstituted with halogen.

R⁸ and R⁹ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group may be substituted with one or more halogen, but moretypically is preferably not substituted with halogen.

In some preferred embodiments, R⁸ and R⁹ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

Preferred Embodiment No. 17

In some embodiments of this invention, the compound has a structurecorresponding to Formula XVII:

A¹, A², and A³ are as defined above for Formula I.

E² is a bond, alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, oralkylcycloalkyl. Any member of this group optionally is substituted.

In some preferred embodiments, E² is a bond, C₁-C₂₀-alkyl, cycloalkyl,C₁-C₁₀-alkylcycloalkyl, cycloalkyl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkylcycloalkyl-C₁-C₁₀-alkyl. Any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, E² is a bond, C₁-C₆-alkyl, orhalo-C₁-C₆-alkyl.

In some preferred embodiments, E² is a bond or C₁-C₆-alkyl.

In some preferred embodiments, E² is a bond.

E⁴ is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally aresubstituted.

In some preferred embodiments, E⁴ is a bond, C₁-C₂₀-alkyl,halo-C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl, or halo-C₂-C₂₀-alkenyl.

In some preferred embodiments, E⁴ is a bond, C₁-C₃-alkyl,halo-C₁-C₃-alkyl, C₂-C₃-alkenyl, or halo-C₂-C₃-alkenyl.

In some preferred embodiments, E⁴ is a bond, C₁-C₃-alkyl, orC₂—C₃-alkenyl.

In some preferred embodiments, E⁴ is a bond.

E⁵ is optionally-substituted heterocyclyl or substituted carbocyclyl.

The E⁵ heterocyclyl optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO₂, —CN, alkyl, haloalkyl, alkoxy, haloalkoxy,alkoxyalkyl, halogen-substituted alkoxyalkyl, —N(R³)(R⁴), —C(O)(R⁵),—S—R³, —S(O)₂—R³, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, andhalogen-substituted carbocyclylalkyl.

In some preferred embodiments, E⁵ is heterocyclyl optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, —CN, C₁-C₈-alkyl, halo-C₁-C₈-alkyl,C₁-C₈-alkoxy, halo-C₁-C₈-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,halogen-substituted C₁-C₈-alkoxy-C₁-C₆-alkyl, —N(R³)(R⁴), —C(O)(R⁵),—S—R³, —S(O)₂—R³, carbocyclyl, halocarbocyclyl, carbocyclyl-C₁-C₆-alkyl,and halogen-substituted carbocyclyl-C₁-C₈-alkyl.

In some preferred embodiments, E⁵ is heterocyclyl optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, —CN, C₁-C₆-alkyl, halo-C₁-C₆-alkyl,C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₁-alkyl,halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R³)(R⁴), —C(O)(R⁵),—S—R³, —S(O)₂—R³, carbocyclyl, halocarbocyclyl, carbocyclyl-C₁-C₆-alkyl,and halogen-substituted carbocyclyl-C₁-C₆-alkyl.

The E⁵ carbocyclyl is substituted with:

-   -   2 or more substituents independently selected from the group        consisting of halogen, —OH, —NO₂, —CN, alkyl, haloalkyl, alkoxy,        haloalkoxy, alkoxyalkyl, halogen-substituted alkoxyalkyl,        —N(R³)(R⁴), —C(O)(R⁵), —S—R³, —S(O)₂—R³, carbocyclyl,        halocarbocyclyl, carbocyclylalkyl, and halogen-substituted        carbocyclylalkyl; or    -   a substituent selected from the group consisting of halogen,        —OH, —NO₂, —CN, —C(O)—O—R³, —S—R³, —S(O)₂—R³, carbocyclyl,        halocarbocyclyl, carbocyclylalkyl, and halogen-substituted        carbocyclylalkyl.

In some preferred embodiments, E⁵ is carbocyclyl substituted with:

-   -   2 or more substituents independently selected from the group        consisting of halogen, —OH, —NO₂, —CN, C₁-C₈-alkyl,        halo-C₁-C₈-alkyl, C₁-C₈-alkoxy, halo-C₁-C₈-alkoxy,        C₁-C₈-alkoxy-C₁-C₈-alkyl, halogen-substituted        C₁-C₈-alkoxy-C₁-C₈-alkyl, —N(R³)(R⁴), —C(O)(R⁵), —S—R³,        —S(O)₂—R³, carbocyclyl, halocarbocyclyl,        carbocyclyl-C₁-C₈-alkyl, and halogen-substituted        carbocyclyl-C₁-C₈-alkyl, or    -   a substituent selected from the group consisting of halogen,        —OH, —NO₂, —CN, —C(O)—O—R³, —S—R³, —S(O)₂—R³, carbocyclyl,        halocarbocyclyl, carbocyclyl-C₁-C₈-alkyl, and        halogen-substituted carbocyclyl-C₁-C₈-alkyl.

In some preferred embodiments, E⁵ is carbocyclyl substituted with:

-   -   2 or more substituents independently selected from the group        consisting of halogen, —OH, —NO₂, —CN, C₁-C₆-alkyl,        halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy,        C₁-C₆-alkoxy-C₁-C₆-alkyl, halogen-substituted        C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R³)(R⁴), —C(O)(R⁵), —S—R³,        —S(O)₂—R³, carbocyclyl, halocarbocyclyl,        carbocyclyl-C₁-C₆-alkyl, and halogen-substituted        carbocyclyl-C₁-C₆-alkyl, or    -   a substituent selected from the group consisting of halogen,        —OH, —NO₂, —CN, —C(O)—O—R³, —S—R³, —S(O)₂—R³, carbocyclyl,        halocarbocyclyl, carbocyclyl-C₁-C₆-alkyl, and        halogen-substituted carbocyclyl-C₁-C₆-alkyl.

R³ and R⁴ are independently selected from the group consisting of —H,alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, andheterocyclylalkyl. Except where the member is —H, any member of thisgroup may be substituted with one or more halogen, but more typically ispreferably not substituted with halogen.

In some preferred embodiments, R³ and R⁴ are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, carbocyclyl,carbocyclyl-C₁-C₈-alkyl, heterocyclyl, and heterocyclyl-C₁-C₈-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, R³ and R⁴ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

R⁵ is —H, alkyl, —O—R⁶, —N(R⁶)(R⁷), carbocyclylalkyl, orheterocyclylalkyl. The alkyl, carbocyclylalkyl, or heterocyclylalkyl maybe substituted with one or more halogen, but more typically ispreferably not substituted with halogen.

In some preferred embodiments, R⁵ is —H, C₁-C₈-alkyl, —O—R⁶, —N(R⁶)(R⁷),carbocyclyl-C₁-C₈-alkyl, or heterocyclyl-C₁-C₈-alkyl. The C₁-C₈-alkyl,carbocyclyl-C₁-C₈-alkyl, or heterocyclyl-C₁-C₈-alkyl may be substitutedwith one or more halogen, but more typically is preferably notsubstituted with halogen.

In some preferred embodiments, R⁵ is —H, C₁-C₆-alkyl, —O—R⁶, —N(R⁶)(R⁷),carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl. The C₁-C₆-alkyl,carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl may be substitutedwith one or more halogen, but more typically is preferably notsubstituted with halogen.

R⁶ and R⁷ are independently selected from the group consisting of —H,alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, andheterocyclylalkyl. Except where the member is —H, any member of thisgroup may be substituted with one or more halogen, but more typically ispreferably not substituted with halogen.

In some preferred embodiments, R⁶and R⁷ are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, carbocyclyl,carbocyclyl-C₁-C₈-alkyl, heterocyclyl, and heterocyclyl-C₁-C₈-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, R⁶ and R⁷ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group may besubstituted with one or more halogen, but more typically is preferablynot substituted with halogen.

In some preferred embodiments, E⁵ is optionally-substitutedheterocyclyl.

In some preferred embodiments, E⁵ is substituted carbocyclyl (preferablysubstituted phenyl). Such compounds include, for example:

Preferred Embodiment No. 18

In some embodiments of this invention, the compound has a structurecorresponding to Formula XVIII:

A¹, A² and A³ are as defined above for Formula I.

E¹ is —O—, —S(O)₂—, —S(O)—, —S—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—, or—C(R¹)(R²)—.

E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, oralkylcycloalkylalkyl. Any member of this group optionally issubstituted.

In some preferred embodiments, E² is C₁-C₂₀-alkyl, cycloalkyl,C₁-C₁₀-alkyl-cycloalkyl, cycloalkyl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkyl-cycloalkyl-C₁-C₁₀-alkyl. Any member of this groupoptionally is substituted with one or more halogen.

In some preferred embodiments, E² is C₁-C₆-alkyl. The alkyl optionallyis substituted with one or more halogen.

E⁵ is substituted heterocyclyl.

In some preferred embodiments, E⁵ is heterocyclyl that is:

-   -   substituted with one or more substituents independently selected        from the group consisting of halogen, —OH, —NO₂, -CN, keto,        C₁-C₈-alkyl, halo-C₁-C₈-alkyl, C₁-C₈-alkoxy, halo-C₁-C₈-alkoxy,        C₁-C₈-alkoxy-C₁-C₈-alkyl, halogen-substituted        C₁-C₈-alkoxy-C₁-C₈-alkyl, —N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵,        —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl, and        carbocyclyl-C₁-C₆-alkyl, and/or    -   substituted on the same atom with two substituents independently        selected from the group consisting of alkyl and haloalkyl, the        two substituents together forming C₅-C₆-cycloalkyl or        halo-C₅-C₆-cycloalkyl.

In some preferred embodiments, E⁵ is heterocyclyl that is:

-   -   substituted with one or more substituents independently selected        from the group consisting of halogen, —OH, —NO₂, —CN, keto,        C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy,        C₁-C₆-alkoxy-C₁-C₆-alkyl, halogen-substituted        C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R⁵)(R⁶), —C(O)(R⁷), —S—R⁵,        —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl,        carbocyclyl-C₁-C₆-alkyl, and halogen-substituted        carbocyclyl-C₁-C₆-alkyl, and/or    -   substituted on the same atom with two substituents independently        selected from the group consisting of alkyl and haloalkyl, the        two substituents together forming C₅-C₆-cycloalkyl or        halo-C₅-C₆-cycloalkyl.

R¹ and R² are independently selected from the group consisting of —H andalkyl. The alkyl optionally is substituted.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, and halo-C₁-C₈-alkyl.

R³ and R⁴ are independently selected from the group consisting of —H,C₁-C₈-alkoxycarbonyl, C₁-C₈-alkylcarbonyl, carbocyclyl-C₁-C₈-alkyl, andC₁-C₈-alkoxycarbonyl.

R⁵ and R⁶ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group optionally is substituted with one or more halogen.

In some preferred embodiments, R⁵ and R⁶ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group optionally issubstituted with one or more halogen.

R⁷ is —H, C₁-C₈-alkyl, —O—R⁸, —N(R⁸)(R⁹), carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl. The alkyl, carbocyclylalkyl, orheterocyclylalkyl may be substituted with one or more halogen.

In some preferred embodiments, R⁷ is —H, C₁-C₆-alkyl, —O—R⁸, —N(R⁸)(R⁹),carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl. The alkyl,carbocyclylalkyl, and heterocyclylalkyl optionally are substituted withone or more halogen.

R⁸ and R⁹ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group optionally is substituted with one or more halogen.

In some preferred embodiments, R⁸ and R⁹ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group optionally issubstituted with one or more halogen.

Compounds of this embodiment include, for example:

Preferred Embodiment No. 19

In some embodiments of this invention, the compound has a structurecorresponding to Formula XIX:

A¹, A², and A³ are as defined above for Formula I.

E¹ is —O—, —S(O)₂—, —S(O)—, —N(R¹)—, —C(O)—N(R¹)—, —N(R)—C(O)—, or—C(R¹)(R²)—.

E² comprises at least two carbon atoms. E² is alkyl, cycloalkyl,alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member ofthis group optionally is substituted.

In some preferred embodiments, E² is C₂-C₂₀-alkyl, cycloalkyl,C₁-C₁₀-alkyl-cycloalkyl, cycloalkyl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkyl-cycloalkyl-C₁-C₁₀-alkyl. Any member of this groupoptionally is substituted with one or more halogen.

In some preferred embodiments, E² is C₂-C₆-alkyl. The alkyl mayoptionally be substituted with one or more halogen.

E⁵ is optionally-substituted heterocyclyl.

In some preferred embodiments, E⁵ is heterocyclyl that is:

-   -   optionally substituted with one or more substituents        independently selected from the group consisting of halogen,        —OH, —NO₂, —CN, keto, C₁-C₈-alkyl, halo-C₁-C₈-alkyl,        C₁-C₈-alkoxy, halo-C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl,        halogen-substituted C₁-C₈-alkoxy-C₁-C₈-alkyl, —N(R⁵)(R⁶),        —C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl, and        carbocyclyl-C₁-C₆-alkyl, and/or    -   optionally substituted on the same atom with two substituents        independently selected from the group consisting of alkyl and        haloalkyl, the two substituents together forming        C₅-C₆-cycloalkyl or halo-C₅-C₆-cycloalkyl.

In some preferred embodiments, E⁵ is heterocyclyl that is:

-   -   optionally substituted with one or more substituents        independently selected from the group consisting of halogen,        —OH, —NO₂, —CN, keto, C₁-C₆-alkyl, halo-C₁-C₆-alkyl,        C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,        halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R¹)(R⁶),        —C(O)(R⁷), —S—R⁵, —S(O)₂—R⁵, carbocyclyl, halocarbocyclyl,        carbocyclyl-C₁-C₆-alkyl, and halogen-substituted        carbocyclyl-C₁-C₆-alkyl, and    -   optionally substituted on the same atom with two substituents        independently selected from the group consisting of alkyl and        haloalkyl, the two substituents together forming        C₅-C₆-cycloalkyl or halo-C₅-C₆-cycloalkyl.

R¹ and R² are independently selected from the group consisting of —H andalkyl. The alkyl optionally is substituted.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, and halo-C₁-C₈-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

R³ and R⁴ are independently selected from the group consisting of —H,C₁-C₈-alkyl, C₁-C₈-alkoxycarbonyl, C₁-C₈-alkylcarbonyl,carbocyclyl-C₁-C₈-alkyl, and carbocyclyl-C₁-C₈-alkoxycarbonyl.

R⁵ and R⁶ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group optionally is substituted with one or more halogen.

In some preferred embodiments, R⁵ and R⁶ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group optionally issubstituted with one or more halogen.

R⁷ is —H, C₁-C₈-alkyl, —O—R⁸, —N(R⁸)(R⁹), carbocyclyl-C₁-C₈-alkyl, orheterocyclyl-C₁-C₈-alkyl. The alkyl, carbocyclylalkyl, andheterocyclylalkyl optionally are substituted with one or more halogen.

In some preferred embodiments, R⁷ is —H, C₁-C₆-alkyl, —O—R⁸, —N(R⁸)(R⁹),carbocyclyl-C₁-C₆-alkyl, or heterocyclyl-C₁-C₆-alkyl. The alkyl,carbocyclylalkyl, and heterocyclyl optionally are substituted with oneor more halogen.

R⁸ and R⁹ are independently selected from the group consisting of —H,C₁-C₈-carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group optionally is substituted with one or more halogen.

In some preferred embodiments, R⁸ and R⁹ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group optionally issubstituted with one or more halogen.

Some particularly preferred compounds include:

Preferred Embodiment No. 20

In some embodiments of this invention, the compound has a structurecorresponding to Formula XX:

A¹, A², and A³ are as defined above for Formula I.

E¹ is —O—, —S(O)₂—, —S(O)—, —S—, —N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—, or—C(R¹)(R²)—.

E² is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, oralkylcycloalkylalkyl. Any member of this group optionally issubstituted.

In some preferred embodiments, E² is C₂-C₂₀-alkyl, cycloalkyl,C₁-C₁₀-alkylcycloalkyl, cycloalkyl-C₁-C₁₀-alkyl, orC₁-C₁₀-alkylcycloalkyl-C₁-C₁₀-alkyl. Any member of this group optionallyis substituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

In some preferred embodiments, E² is C₂-C₆-alkyl. The alkyl mayoptionally be substituted with one or more halogen.

E³ is —C(O)—, —O—(CO)—, —C(O)—O—, —C(NR³)—, —N(R⁴)—, —N(R⁴)—C(NR³)—,—C(NR³)—N(R⁴)—, —C(O)—N(R⁴)—, —N(R⁴)—C(O), —N(R⁴)—C(O)—N(R⁵)—, —S—,—S(O)—, —N(R⁴)—S(O)₂—, —S(O)₂—N(R⁴)—, —C(O)N(R⁴)—N(R⁵)—C(O)—,—C(R⁴)(R⁶)—C(O)—, or —C(R⁷)(R⁸).

E⁴ is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally aresubstituted.

In some preferred embodiments, E⁴ is a bond, C₁-C₂₀-alkyl, orC₂-C₂₀-alkenyl. The alkyl and alkenyl optionally are substituted withone or more substituents independently selected from the groupconsisting of halogen, and carbocyclyl. The carbocyclyl, in turn,optionally is substituted with one or more substituents independentlyselected from the group consisting of halogen, —OH, —NO₂, —CN,C₁-C₈-alkyl, C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl, carbocyclyl,carbocyclyl-C₁-C₈-alkyl, halo-C₁-C₈-alkyl, halo-C₁-C₈-alkoxy,halogen-substituted C₁-C₈-alkoxy-C₁-C₈-alkyl, halocarbocyclyl, andhalogen-substituted carbocyclyl-C₁-C₈-alkyl.

In some preferred embodiments, E⁴ is a bond, C₁-C₃-alkyl, orC₂-C₃-alkenyl. The alkyl and alkenyl optionally are substituted with oneor more substituents independently selected from the group consisting ofhalogen and carbocyclyl. The carbocyclyl, in turn, optionally issubstituted with one or more substituents independently selected fromthe group consisting of halogen, —OH, —NO₂, —CN, C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy,halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl, halocarbocyclyl, andhalogen-substituted carbocyclyl-C₁-C₆-alkyl.

E⁵ is carbocyclyl or heterocyclyl. The carbocyclyl and heterocyclyl are:

-   -   substituted with a substituent selected from the group        consisting of optionally-substituted carbocyclyl,        optionally-substituted carbocyclylalkyl, optionally-substituted        heterocyclyl, and optionally-substituted heterocyclylalkyl, and    -   optionally substituted with one or more substituents        independently selected from the group consisting of halogen,        —OH, —NO₂, —CN, alkyl, alkoxy, alkoxyalkyl, —N(R¹¹)(R¹²),        —C(O)(R¹³), —S—R¹¹, —S(O)₂—R¹¹, carbocyclyl, carbocyclylalkyl,        haloalkyl, haloalkoxy, halogen-substituted alkoxyalkyl,        halocarbocyclyl, halogen-substituted carbocyclylalkyl,        hydroxycarbocyclyl, and heteroaryl.

In some preferred embodiments, E⁵ is carbocyclyl or heterocyclyl. Thecarbocyclyl and heterocyclyl are:

-   -   substituted with a substituent selected from the group        consisting of optionally-substituted carbocyclyl,        optionally-substituted carbocyclyl-C₁-C₈-alkyl,        optionally-substituted heterocyclyl, and optionally-substituted        heterocyclyl-C₁-C₈-alkyl, and    -   optionally substituted with one or more substituents        independently selected from the group consisting of halogen,        —OH, —NO₂, —CN, C₁-C₈-alkyl, C₁-C₈-alkoxy,        C₁-C₈-alkoxy-C₁-C₈-alkyl, —N(R¹¹)(R¹²), —C(O)(R³), —S—R¹¹,        —S(O)₂—R¹¹, carbocyclyl, carbocyclyl-C₁-C₈-alkyl,        halo-C₁-C₈-alkyl, halo-C₁-C₈-alkoxy, halogen-substituted        C₁-C₈-alkoxy-C₁-C₈-alkyl, halocarbocyclyl, halogen-substituted        carbocyclyl-C₁-C₈-alkyl, hydroxycarbocyclyl, and heteroaryl.

In some preferred embodiments, E⁵ is carbocyclyl or heterocyclyl,wherein the carbocyclyl and heterocyclyl are:

-   -   substituted with a substituent selected from the group        consisting of optionally-substituted carbocyclyl,        optionally-substituted carbocyclyl-C₁-C₆-alkyl,        optionally-substituted heterocyclyl, and optionally-substituted        heterocyclyl-C₁-C₆-alkyl, and    -   optionally substituted with one or more substituents        independently selected from the group consisting of halogen,        —OH, —NO₂, —CN, C₁-C₆-alkyl, C₁-C₆-alkoxy,        C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R¹¹)(R¹²), —C(O)(R¹³), —S—R¹¹,        —S(O)₂—R¹¹, carbocyclyl, carbocyclyl-C₁-C₆-alkyl,        halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, halogen-substituted        C₁-C₆-alkoxy-C₁-C₆-alkyl, halocarbocyclyl, halogen substituted        carbocyclyl-C₁-C₆-alkyl, hydroxycarbocyclyl, and heteroaryl.

R¹ and R² are independently selected from the group consisting of —H andalkyl. The alkyl optionally is substituted.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, and halo-C₁-C₈-alkyl.

In some preferred embodiments, R¹ and R² are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl.

R³ is —H or —OH.

R⁴ and R⁵ are independently selected from the group consisting of —H,alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, andheterocyclylatkyl. Except where the member is —H, any member of thisgroup optionally is substituted.

In some preferred embodiments, R⁴ and R⁵ are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, carbocyclyl,carbocyclyl-C₁-C₈-alkyl, heterocyclyl, and heterocyclyl-C₁-C₈-alkyl.Except where the member is —H, any member of this group optionally issubstituted with one or more halogen.

In some preferred embodiments, R⁴ and R⁵ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group optionally issubstituted with one or more halogen.

R⁶ is —CN or —OH.

R⁷ is —H, halogen, —OH, alkyl, alkoxy, or alkoxyalkyl. The alkyl,alkoxy, and alkoxyalkyl optionally are substituted.

In some preferred embodiments, R⁷ is —H, halogen, —OH, C₁-C₈-alkyl,C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl, halo-C₁-C₈-alkyl,halo-C₁-C₈-alkoxy, or halogen-substituted C₁-C₈-alkoxy-C₁-C₈-alkyl.

In some preferred embodiments, R⁷ is —H, halogen, —OH, C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, halo-C₁-C₆-alkyl,halo-C₁-C₆-alkoxy, or halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl.

R⁸ is —OH or alkoxy. The alkoxy optionally is substituted.

In some preferred embodiments, R⁸ is —OH, C₁-C₈-alkoxy, orhalo-C₁-C₈-alkoxy.

In some preferred embodiments, R⁸ is —OH, C₁-C₆-alkoxy, orhalo-C₁-C₆-alkoxy.

R⁹ and R¹⁰ are independently selected from the group consisting of —H,C₁-C₈-alkyl, C₁-C₈-alkoxycarbonyl, C₁-C₈-alkylcarbonyl,carbocyclyl-C₁-C₈-alkyl, and carbocyclyl-C₁-C₈-alkoxycarbonyl.

R¹¹ and R¹² are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group optionally is substituted with one or more halogen.

In some preferred embodiments, R¹¹ and R¹² are independently selectedfrom the group consisting of —H, C₁-C₈-alkyl, carbocyclyl,carbocyclyl-C₁-C₈-alkyl, heterocyclyl, and heterocyclyl-C₁-C₈-alkyl.Except where the member is —H, any member of this group optionally issubstituted with one or more halogen.

In some preferred embodiments, R¹¹ and R¹² are independently selectedfrom the group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group optionally issubstituted with one or more halogen.

R¹³ is —H, C₁—C₈-alkyl, —O—R¹⁴, —N(R¹⁴)(R¹⁵), carbocyclyl-C₁-C₈-alkyl,heterocyclyl-C₁-C₈-alkyl, halo-C₁-C₈-alkyl, halogen-substitutedcarbocyclyl-C₁-C₈-alkyl, or halogen-substitutedheterocyclyl-C₁-C₈-alkyl.

In some preferred embodiments, R¹³ is of —H, C₁-C₆-alkyl, —O—R¹⁴,—N(R¹⁴)(R₁₅), carbocyclyl-C₁-C₆-alkyl, heterocyclyl-C₁-C₆-alkyl,halo-C₁-C₆-alkyl, halogen-substituted carbocyclyl-C₁-C₆-alkyl, orhalogen-substituted heterocyclyl-C₁-C₆-alkyl.

R¹⁴ and R¹⁵ are independently selected from the group consisting of —H,C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl, heterocyclyl, andheterocyclyl-C₁-C₈-alkyl. Except where the member is —H, any member ofthis group optionally is substituted with one or more halogen.

In some preferred embodiments, R¹⁴ and R¹⁵ are independently selectedfrom the group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, and heterocyclyl-C₁-C₆-alkyl.Except where the member is —H, any member of this group optionally issubstituted with one or more halogen.

Some preferred compounds include, for example:

Preferred MMP Selectivities

The hydroxamic acid compound or salt preferably has an inhibitoryactivity against MMP-1 or MMP-14 that is substantially less than itsinhibitory activity against MMP-2, MMP-9, or MMP-13. In other words, thehydroxamic acid compound or salt preferably has an in inhibitionconstant (K_(i)) against at least one of MMP-2, MMP-9, and MMP-13 thatis no greater than about 0.1 times its inhibition constant(s) against atleast one of MMP-1 and MMP-14. The inhibition constant of a compound orsalt thereof may be determined using an in vitro inhibition assay, suchas the K_(i) assay described below in Examples 55-89.

In some particularly preferred embodiments, the hydroxamic acid compoundor salt preferably has a K_(i) against MMP-2 that is no greater thanabout 0.1 (more preferably no greater than about 0.01, even morepreferably no greater than about 0.001, still more preferably no greaterthan about 0.0001, and still even more preferably no greater than about0.00001) times its K_(i)(s) against one or both of MMP-1 and MMP-14.

In some particularly preferred embodiments, the hydroxamic acid compoundor salt preferably has a K_(i) against MMP-9 that is no greater thanabout 0.1 (more preferably no greater than about 0.01, even morepreferably no greater than about 0.001, still more preferably no greaterthan about 0.0001, and still even more preferably no greater than about0.00001) times its K_(i)(s) against one or both of MMP-1 and MMP-14.

In some particularly preferred embodiments, the hydroxamic acid compoundor salt preferably has a K_(i) against MMP-13 that is no greater thanabout 0.1 (more preferably no greater than about 0.01, even morepreferably no greater than about 0.001, still more preferably no greaterthan about 0.0001, and still even more preferably no greater than about0.00001) times its K_(i)(s) against one or both of MMP-1 and MMP-14. Itis believed that such a selectivity profile is often particularlypreferred when preventing or treating, for example, a cardiovascularcondition or arthritis.

In some particularly preferred embodiments, the hydroxamic acid compoundor salt preferably has K_(i)'s against both MMP-2 and MMP-9 that are nogreater than about 0.1 (more preferably no greater than about 0.01, evenmore preferably no greater than about 0.001, still more preferably nogreater than about 0.0001, and still even more preferably no greaterthan about 0.00001) times its K_(i)(s) against one or both of MMP-1 andMMP-14. It is believed that such a selectivity profile is oftenparticularly preferred when preventing or treating, for example, cancer,a cardiovascular condition, or an ophthalmologic condition.

In some particularly preferred embodiments, the hydroxamic acid compoundor salt preferably has K_(i)'s against all of MMP-2, MMP-9, and MMP-13that are no greater than about 0.1 (more preferably no greater thanabout 0.01, even more preferably no greater than about 0.001, still morepreferably no greater than about 0.0001, and still even more preferablyno greater than about 0.00001) times its K_(i)(s) against one or both ofMMP-1 and MMP-14. It is believed that such a selectivity profile isoften particularly preferred when preventing or treating, for example,cancer, a cardiovascular condition, arthritis, or an ophthalmologiccondition.

In some particularly preferred embodiments, the hydroxamic acid compoundor salt preferably has a K_(i) against MMP-2 that is no greater thanabout 0.1 (more preferably no greater than about 0.01, even morepreferably no greater than about 0.001, still more preferably no greaterthan about 0.0001, and still even more preferably no greater than about0.00001) times its K_(i)'s against both MMP-1 and MMP-14.

In some particularly preferred embodiments, the hydroxamic acid compoundor salt preferably has a K_(i) against MMP-9 that is no greater thanabout 0.1 (more preferably no greater than about 0.01, even morepreferably no greater than about 0.001, still more preferably no greaterthan about 0.0001, and still even more preferably no greater than about0.00001) times its K_(i)'s against both MMP-1 and MMP-14.

In some particularly preferred embodiments, the hydroxamic acid compoundor salt preferably has a K_(i) against MMP-13 that is no greater thanabout 0.1 (more preferably no greater than about 0.01, even morepreferably no greater than about 0.001, still more preferably no greaterthan about 0.0001, and still even more preferably no greater than about0.00001) times its K_(i)'s against both MMP-1 and MMP-14. It is believedthat such a selectivity profile is often particularly preferred whenpreventing or treating, for example, a cardiovascular condition orarthritis.

In some particularly preferred embodiments, the hydroxamic acid compoundor salt preferably has K_(i)'s against both MMP-2 and MMP-9 that are nogreater than about 0.1 (more preferably no greater than about 0.01, evenmore preferably no greater than about 0.001, still more preferably nogreater than about 0.0001, and still even more preferably no greaterthan about 0.00001) times its K_(i)'s against both of MMP-1 and MMP-14.It is believed that such a selectivity profile is often particularlypreferred when preventing or treating, for example, cancer, acardiovascular condition, or an ophthalmologic condition.

In some particularly preferred embodiments, the hydroxamic acid compoundor salt preferably has K_(i)'s against all of MMP-2, MMP-9, and MMP-13that are no greater than about 0.1 (more preferably no greater thanabout 0.01, even more preferably no greater than about 0.001, still morepreferably no greater than about 0.0001, and still even more preferablyno greater than about 0.00001) times its K_(i)'s against both of MMP-1and MMP-14. It is believed that such a selectivity profile is oftenparticularly preferred when preventing or treating, for example, cancer,a cardiovascular condition, arthritis, or an ophthalmologic condition.

The activity and selectivity of a hydroxamic acid compound or salt mayalternatively be determined using an in vitro IC₅₀ assay, such as theIC₅₀ assay described below in Examples 55-89. In that instance, thehydroxamic acid compound or salt preferably has an IC₅₀ value against atleast one of MMP-2, MMP-9, and MMP-13 that is no greater than about 0.1times its IC₅₀ value(s) against at least one of MMP-1 and MMP-14.

In some particularly preferred embodiments, the hydroxamic acid compoundor salt preferably has an IC₅₀ value against MMP-2 that is no greater-than about 0.1 (more preferably no greater than about 0.01, even morepreferably no greater than about 0.001, still more preferably no greaterthan about 0.0001, and still even more preferably no greater than about0.00001) times its IC₅₀ value(s) against one or both of MMP-1 andMMP-14.

In some particularly preferred embodiments, the hydroxamic acid compoundor salt preferably has an IC50 value against MMP-9 that is no greaterthan about 0.1 (more preferably no greater than about 0.01, even morepreferably no greater than about 0.001, still more preferably no greaterthan about 0.0001, and still even more preferably no greater than about0.00001) times its IC₅₀ value(s) against one or both of MMP-1 andMMP-14.

In some particularly preferred embodiments, the hydroxamic acid compoundor salt preferably has an IC50 value against MMP-13 that is no greaterthan about 0.1 (more preferably no greater than about 0.01, even morepreferably no greater than about 0.001, still more preferably no greaterthan about 0.0001, and still even more preferably no greater than about0.00001) times its IC₅₀ value(s) against one or both of MMP-1 andMMP-14. It is believed that such a selectivity profile is oftenparticularly preferred when preventing or treating, for example, acardiovascular condition or arthritis.

In some particularly preferred embodiments, the hydroxamic acid compoundor salt preferably has IC₅₀ values against both MMP-2 and MM-9 that areno greater than about 0.1 (more preferably no greater than about 0.01,even more preferably no greater than about 0.001, still more preferablyno greater than about 0.0001, and still even more preferably no greaterthan about 0.00001) times its IC₅₀ value(s) against one or both of MMP-1and MMP-14. It is believed that such a selectivity profile is oftenparticularly preferred when preventing or treating, for example, cancer,a cardiovascular condition, or an ophthalmologic condition.

In some particularly preferred embodiments, the hydroxamic acid compoundor salt preferably has IC₅₀ values against all of MMP-2, MMP-9, andMMP-13 that are no greater than about 0.1 (more preferably no greaterthan about 0.01, even more preferably no greater than about 0.001, stillmore preferably no greater than about 0.0001, and still even morepreferably no greater than about 0.00001) times its IC₅₀ value(s)against one or both of MMP-1 and MMP-14. It is believed that such aselectivity profile is often particularly preferred when preventing ortreating, for example, cancer, a cardiovascular condition, arthritis, oran ophthalmologic condition.

In some particularly preferred embodiments, the hydroxamic acid compoundor salt preferably has an IC₅₀ value against MMP-2 that is no greaterthan about 0.1 (more preferably no greater than about 0.01, even morepreferably no greater than about 0.001, still more preferably no greaterthan about 0.0001, and still even more preferably no greater than about0.00001) times its IC₅₀ values against both MMP-1 and MMP-14.

In some particularly preferred embodiments, the hydroxamic acid compoundor By salt preferably has an IC₅₀ value against MMP-9 that is no greaterthan about 0.1 (more preferably no greater than about 0.01, even morepreferably no greater than about 0.001, still more preferably no greaterthan about 0.0001, and still even more preferably no greater than about0.00001) times its IC₅₀ values against both MMP-1 and MMP-14.

In some particularly preferred embodiments, the hydroxamic acid compoundor salt preferably has an IC₅₀ value against MMP-13 that is no greaterthan about 0.1 (more preferably no greater than about 0.01, even morepreferably no greater than about 0.001, still more preferably no greaterthan about 0.0001, and still even more preferably no greater than about0.00001) times its IC₅₀ values against both MMP-1 and MMP-14. It isbelieved that such a selectivity profile is often particularly preferredwhen preventing or treating, for example, a cardiovascular condition orarthritis.

In some particularly preferred embodiments, the hydroxamic acid compoundor salt preferably has IC₅₀ values against both MMP-2 and MMP-9 that areno greater than about 0.1 (more preferably no greater than about 0.01,even more preferably no greater than about 0.001, still more preferablyno greater than about 0.0001, and still even more preferably no greaterthan about 0.00001) times its IC₅₀ values against both of MMP-1 andMMP-14. It is believed that such a selectivity profile is oftenparticularly preferred when preventing or treating, for example, cancer,a cardiovascular condition, or an ophthalmologic condition.

In some particularly preferred embodiments, the hydroxamic acid compoundor salt preferably has IC₅₀ values against all of MMP-2, MMP-9, andMMP-13 that are no greater than about 0.1 (more preferably no greaterthan about 0.01, even more preferably no greater than about 0.001, stillmore preferably no greater than about 0.0001, and still even morepreferably no greater than about 0.00001) times its IC₅₀ values againstboth of MMP-1 and MMP-14. It is believed that such a selectivity profileis often particularly preferred when preventing or treating, forexample, cancer, a cardiovascular condition, arthritis, or anophthalmologic condition.

B. Salts of the Compounds of this Invention

The compounds of this invention can be used in the form of salts derivedfrom inorganic or organic acids. Depending on the particular compound, asalt of the compound can be advantageous due to one or more of thesalt's physical properties, such as enhanced pharmaceutical stability indiffering temperatures and humidities, or a desirable solubility inwater or oil. In some instances, a salt of a compound also may be usedas an aid in the isolation, purification, and/or resolution of thecompound.

Where a salt is intended to be administered to a patient (as opposed to,for example, being used in an in vitro context), the salt preferably ispharmaceutically acceptable. Pharmaceutically acceptable salts includesalts commonly used to form alkali metal salts and to form additionsalts of free acids or free bases. In general, these salts typically maybe prepared by conventional means with a compound of this invention byreacting, for example, the appropriate acid or base with the compound.

Pharmaceutically-acceptable acid addition salts of the compounds of thisinvention may be prepared from an inorganic or organic acid. Examples ofsuitable inorganic acids include hydrochloric, hydrobromic acid,hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Suitableorganic acids generally include, for example, aliphatic, cycloaliphatic,aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes oforganic acids. Specific examples of suitable organic acids includeacetate, trifluoroacetate, formate, propionate, succinate, glycolate,gluconate, digluconate, lactate, malate, tartaric acid, citrate,ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate,glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate,p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate),ethanesulfonate, benzenesulfonate, pantothenate,2-hydroxyethanesulfonate, sulfanilate, cyclohexylaminosulfonate, algenicacid, β-hydroxybutyric acid, galactarate, galacturonate, adipate,alginate, butyrate, camphorate, camphorsulfonate,cyclopentanepropionate, dodecylsulfate, glycoheptanoate,glycerophosphate, heptanoate, hexanoate, nicotinate,2-naphthalesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate,picrate, pivalate, thiocyanate, tosylate, and undecanoate.

Pharmaceutically-acceptable base addition salts of the compounds of thisinvention include, for example, metallic salts and organic salts.Preferred metallic salts include alkali metal (group Ia) salts, alkalineearth metal (group IIa) salts, and other physiologically acceptablemetal salts. Such salts may be made from aluminum, calcium, lithium,magnesium, potassium, sodium, and zinc. Preferred organic salts can bemade from amines, such as tromethamine, diethylamine,N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine,ethylenediamine, meglumine (N-methylglucamine), and procaine. Basicnitrogen-containing groups can be quaternized with agents such as loweralkyl (C₁-C₆) halides (e.g., methyl, ethyl, propyl, and butyl chlorides,bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl,dibuytl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl,myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides(e.g., benzyl and phenethyl bromides), and others.

Particularly preferred salts of the compounds of this invention includehydrochloric acid (HCl) salts and trifluoroacetate (CF₃COOH or TFA)salts.

C. Preventing or Treating Conditions Using the Compounds and Salts ofthis Invention

One embodiment of this invention is directed to a process for preventingor treating a pathological condition associated with MMP activity in amammal (e.g., a human, companion animal, farm animal, laboratory animal,zoo animal, or wild animal) having or disposed to having such acondition. Such a condition may be, for example, tissue destruction, afibrotic disease, pathological matrix weakening, defective injuryrepair, a cardiovascular disease, a pulmonary disease, a kidney disease,a liver disease, an ophthalmologic disease, or a central nervous systemdisease. Specific examples of such conditions include osteoarthritis,rheumatoid arthritis, septic arthritis, tumor invasion, tumormetastasis, tumor angiogenesis, a decubitis ulcer, a gastric ulcer, acorneal ulcer, periodontal disease, liver cirrhosis, fibrotic lungdisease, otosclerosis, atherosclerosis, multiple sclerosis, dilatedcardiomyopathy, epidermal ulceration, epidermolysis bullosa, aorticaneurysm, weak injury repair, an adhesion, scarring, congestive heartfailure, post myocardial infarction, coronary thrombosis, emphysema,proteinuria, bone disease, chronic obstructive pulmonary diseases, andAlzheimer's disease.

In some particularly preferred embodiments, the condition comprisesarthritis.

In some particularly preferred embodiments, the condition comprisestumor invasion, tumor metastasis, or tumor angiogenesis.

In some particularly preferred embodiments, the condition comprisesperiodontal disease.

In some particularly preferred embodiments, the condition comprisesatherosclerosis.

In some particularly preferred embodiments, the condition comprisesmultiple sclerosis.

In some particularly preferred embodiments, the condition comprisesdilated cardiomyopathy.

In some particularly preferred embodiments, the condition comprises postmyocardial infarction.

In some particularly preferred embodiments, the condition comprisescongestive heart failure.

In some particularly preferred embodiments, the condition compriseschronic obstructive pulmonary disease.

The condition may alternatively (or additionally) be associated withTNF-α convertase activity. Examples of such a condition includeinflammation (e.g., rheumatoid arthritis), autoimmune disease, graftrejection, multiple sclerosis, a fibrotic disease, cancer, an infectiousdisease (e.g., malaria, mycobacterial infection, meningitis, etc.),fever, psoriasis, a cardiovascular disease (e.g., post-ischemicreperfusion injury and congestive heart failure), a pulmonary disease,hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage,acute phase responses like those seen with infections and sepsis andduring shock (e.g., septic shock, hemodynamic shock, etc.), cachexia,and anorexia.

The condition may alternatively (or additionally) be associated withaggrecanase activity. Examples of such a condition include inflammationdiseases (e.g., osteoarthritis, rheumatoid arthritis, joint injury,reactive arthritis, acute pyrophosphate arthritis, and psoriaticarthritis) and cancer.

In this patent, the phrase “preventing a condition” means reducing therisk of (or delaying) the onset of the condition in a mammal that doesnot have the condition, but is predisposed to having the condition. Incontrast, the phrase “treating a condition” means ameliorating,suppressing, or eradicating an existing condition. The pathologicalcondition may be (a) the result of pathological MMP activity itself,and/or (b) affected by MMP activity (e.g., diseases associated withTNF-α).

A wide variety of methods may be used alone or in combination toadminister the hydroxamic acids and salt thereof described above. Forexample, the hydroxamic acids or salts thereof may be administeredorally, parenterally, by inhalation spray, rectally, or topically.

Typically, a compound (or pharmaceutically acceptable salt thereof)described in this patent is administered in an amount effective toinhibit a target MMP(s) or aggrecanase. The target MMP is/are typicallyMMP-2, MMP-9, and/or MMP-13, with MMP-13 often being a particularlypreferred target. The preferred total daily dose of the hydroxamic acidor salt thereof (administered in single or divided doses) is typicallyfrom about 0.001 to about 100 mg/kg, more preferably from about 0.001 toabout 30 mg/kg, and even more preferably from about 0.01 to about 10mg/kg (i.e., mg hydroxamic acid or salt thereof per kg body weight).Dosage unit compositions can contain such amounts or submultiplesthereof to make up the daily dose. In many instances, the administrationof the compound or salt will be repeated a plurality of times. Multipledoses per day typically may be used to increase the total daily dose, ifdesired.

Factors affecting the preferred dosage regimen include the type, age,weight, sex, diet, and condition of the patient; the severity of thepathological condition; the route of administration; pharmacologicalconsiderations, such as the activity, efficacy, pharmacokinetic, andtoxicology profiles of the particular hydroxamic acid or salt thereofemployed; whether a drug delivery system is utilized; and whether thehydroxamic acid or salt thereof is administered as part of a drugcombination. Thus, the dosage regimen actually employed can vary widely,and, therefore, can deviate from the preferred dosage regimen set forthabove.

D. Pharmaceutical Compositions Containing the Compounds and salts ofthis Invention

This invention also is directed to pharmaceutical compositionscomprising a hydroxamic acid or salt thereof described above, and tomethods for making pharmaceutical compositions (or medicaments)comprising a hydroxamic acid or salt thereof described above.

The preferred composition depends on the method of administration, andtypically comprises one or more conventional pharmaceutically acceptablecarriers, adjuvants, and/or vehicle. Formulation of drugs is generallydiscussed in, for example, Hoover, John E., Remington's PharmaceuticalSciences (Mack Publishing Co., Easton, Pa.: 1975). See also, Liberman,H. A. See also, Lachman, L., eds., Pharmaceutical Dosage Form (MarcelDecker, New York, N.Y., 1980).

Solid dosage forms for oral administration include, for example,capsules, tablets, pills, powders, and granules. In such solid dosageforms, the hydroxamic acids or salts thereof are ordinarily combinedwith one or more adjuvants. If administered per os, the hydroxamic acidsor salts thereof can be mixed with lactose, sucrose, starch powder,cellulose esters of alkanoic acids, cellulose alkyl esters, talc,stearic acid, magnesium stearate, magnesium oxide, sodium and calciumsalts of phosphoric and sulfuric acids, gelatin, acacia gum, sodiumalginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and thentableted or encapsulated for convenient administration. Such capsules ortablets can contain a controlled-release formulation, as can be providedin a dispersion of the hydroxamic acid or salt thereof inhydroxypropylmethyl cellulose. In the case of capsules, tablets, andpills, the dosage forms also can comprise buffering agents, such assodium citrate, or magnesium or calcium carbonate or bicarbonate.Tablets and pills additionally can be prepared with enteric coatings.

Liquid dosage forms for oral administration include, for example,pharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art (e.g.,water). Such compositions also can comprise adjuvants, such as wetting,emulsifying, suspending, flavoring (e.g., sweetening), and/or perfumingagents.

“Parenteral administration” includes subcutaneous injections,intravenous injections, intramuscular injections, intrasternalinjections, and infusion. Injectable preparations (e.g., sterileinjectable aqueous or oleaginous suspensions) can be formulatedaccording to the known art using suitable dispersing, wetting agents,and/or suspending agents. Acceptable vehicles and solvents include, forexample, water, 1,3-butanediol, Ringer's solution, isotonic sodiumchloride solution, bland fixed oils (e.g., synthetic mono- ordiglycerides), fatty acids (e.g., oleic acid), dimethyl acetamide,surfactants (e.g., ionic and non-ionic detergents), and/or polyethyleneglycols.

Formulations for parenteral administration may, for example, be preparedfrom sterile powders or granules having one or more of the carriers ordiluents mentioned for use in the formulations for oral administration.The hydroxamic acids or salts thereof can be dissolved in water,polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseedoil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/orvarious buffers.

Suppositories for rectal administration can be prepared by, for example,mixing the drug with a suitable nonirritating excipient that is solid atordinary temperatures, but liquid at the rectal temperature and willtherefore melt in the rectum to release the drug. Suitable excipientsinclude, for example, such as cocoa butter; synthetic mono-, di-, ortriglycerides; fatty acids; and/or polyethylene glycols

“Topical administration” includes the use of transdermal administration,such as transdermal patches or iontophoresis devices.

Other adjuvants and modes of administration well-known in thepharmaceutical art may also be used.

E. Definitions

The term “alkyl” (alone or in combination with another term(s)) means astraight-or branched-chain saturated hydrocarbyl typically containingfrom 1 to about 20 carbon atoms, more typically from 1 to about 8 carbonatoms, and even more typically from 1 to about 6 carbon atoms. Examplesof such substituents include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl,octyl, and the like.

The term “alkenyl” (alone or in combination with another term(s)) meansa straight- or branched-chain hydrocarbyl containing one or more doublebonds and typically from 2 to about 20 carbon atoms, more typically fromabout 2 to about 8 carbon atoms, and even more typically from about 2 toabout 6 carbon atoms. Examples of such substituents include ethenyl(vinyl); 2-propenyl; 3-propenyl; 1,4-pentadienyl; 1,4-butadienyl;1-butenyl; 2-butenyl; 3-butenyl; decenyl; and the like.

The term “alkynyl” (alone or in combination with another term(s)) meansa straight- or branched-chain hydrocarbyl containing one or more triplebonds and typically from 2 to about 20 carbon atoms, more typically fromabout 2 to about 8 carbon atoms, and even more typically from about 2 toabout 6 carbon atoms. Examples of such substituents include ethynyl,2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, andthe like.

The term “carbocyclyl” (alone or in combination with another term(s))means a saturated cyclic (i.e., “cycloalkyl”), partially saturatedcyclic, or aryl hydrocarbyl containing from 3 to 14 carbon ring atoms(“ring atoms” are the atoms bound together to form the ring or rings ofa cyclic group). A carbocyclyl may be a single ring, which typicallycontains from 3 to 6 ring atoms. Examples of such single-ringcarbocyclyls include cyclopropanyl, cyclobutanyl, cyclopentyl,cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl,cyclohexadienyl, and phenyl. A carbocyclyl alternatively may be 2 or 3rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (alsoknown as “tetralinyl”), indenyl, isoindenyl, indanyl, bicyclodecanyl,anthracenyl, phenanthrene, benzonaphthenyl (also known as “phenalenyl”),fluoreneyl, decalinyl, and norpinanyl.

The term “cycloalkyl” (alone or in combination with another term(s))means a saturated cyclic hydrocarbyl containing from 3 to 14 carbon ringatoms. A cycloalkyl may be a single carbon ring, which typicallycontains from 3 to 6 carbon ring atoms. Examples of single-ringcycloalkyls include cyclopropyl (or “cyclopropanyl”), cyclobutyl (or“cyclobutanyl”), cyclopentyl (or “cyclopentanyl”), and cyclohexyl (or“cyclohexanyl”). A cycloalkyl alternatively may be 2 or 3 carbon ringsfused together, such as, decalinyl or norpinanyl.

The term “aryl” (alone or in combination with another term(s)) means anaromatic carbocyclyl containing from 6 to 14 carbon ring atoms. Examplesof aryls include phenyl, naphthalenyl, and indenyl.

In some instances, the number of carbon atoms in a hydrocarbyl (e.g.,alkyl, alkenyl, alkynyl, or cycloalkyl) is indicated by the prefix“C_(x)-C_(y)—”, wherein x is the minimum and y is the maximum number ofcarbon atoms in the substituent. Thus, for example, “C₁-C₆-alkyl” refersto an alkyl containing from 1 to 6 carbon atoms. Illustrating further,C₃-C₆-cycloalkyl means a saturated hydrocarbyl ring containing from 3 to6 carbon ring atoms.

The term “hydrogen” (alone or in combination with another term(s)) meansa hydrogen radical, and may be depicted as —H.

The term “hydroxy” (alone or in combination with another term(s)) means—OH.

The term “nitro” (alone or in combination with another term(s)) means—NO₂.

The term “cyano” (alone or in combination with another term(s)) means—CN, which also may be depicted as:

The term “keto” (alone or in combination with another term(s)) means anoxo radical, and may be depicted as ═O.

The term “carboxy” (alone or in combination with another term(s)) means—C(O)—OH, which also may be depicted as:

The term “amino” (alone or in combination with another term(s)) means—NH₂. The term “monosubstituted amino” (alone or in combination withanother term(s)) means an amino wherein one of the hydrogen radicals isreplaced by a non-hydrogen substituent. The term “disubstituted amino”(alone or in combination with another term(s)) means an amino whereinboth of the hydrogen atoms are replaced by non-hydrogen substituents,which may be identical or different.

The term “halogen” (alone or in combination with another tern(s)) meansa fluorine radical (which may be depicted as —F), chlorine radical(which may be depicted as —Cl), bromine radical (which may be depictedas —Br), or iodine radical (which may be depicted as —I). Typically, afluorine radical or chlorine radical is preferred, with a fluorineradical often being particularly preferred.

If a substituent is described as being “substituted”, a non-hydrogenradical is in the place of a hydrogen radical on a carbon or nitrogen ofthe substituent. Thus, for example, a substituted alkyl substituent isan alkyl substituent wherein at least one non-hydrogen radical is in theplace of a hydrogen radical on the alkyl substituent. To illustrate,monofluoroalkyl is alkyl substituted with a fluoro radical, anddifluoroalkyl is alkyl substituted with two fluoro radicals. It shouldbe recognized that if there are more than one substitutions on asubstituent, each non-hydrogen radical may be identical or different(unless otherwise stated).

If a substituent is described as being “optionally substituted”, thesubstituent may be either (1) substituted, or (2) not substituted.

This specification uses the terms “substituent” and “radical”interchangeably.

The prefix “halo” indicates that the substituent to which the prefix isattached is substituted with one or more independently selected halogenradicals. For example, haloalkyl means an alkyl wherein at least onehydrogen radical is replaced with a halogen radical. Examples ofhaloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl,difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like.Illustrating further, “haloalkoxy” means an alkoxy wherein at least onehydrogen radical is replaced by a halogen radical. Examples ofhaloalkoxy substituents include chloromethoxy, 1-bromoethoxy,fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as“perfluoromethyoxy”), 1,1,1,-trifluoroethoxy, and the like. It should berecognized that if a substituent is substituted by more than one halogenradical, those halogen radicals may be identical or different (unlessstated otherwise).

The prefix “perhalo” indicates that every hydrogen radical on thesubstituent to which the prefix is attached is replaced withindependently selected halogen radicals, i.e., each hydrogen radical onthe substituent is replaced with a halogen radical. If all the halogenradicals are identical, the prefix typically will identify the halogenradical. Thus, for example, the term “perfluoro” means that everyhydrogen radical on the substituent to which the prefix is attached issubstituted with a fluorine radical. To illustrate, the term“perfluoroalkyl” means an alkyl wherein a fluorine radical is in theplace of each hydrogen radical. Examples of perfluoroalkyl substituentsinclude trifluoromethyl (—CF₃), perfluorobutyl, perfluoroisopropyl,perfluorododecyl, perfluorodecyl, and the like. To illustrate further,the term “perfluoroalkoxy” means an alkoxy wherein each hydrogen radicalis replaced with a fluorine radical. Examples of perfluoroalkoxysubstituents include trifluoromethoxy (—O—CF₃), perfluorobutoxy,perfluoroisopropoxy, perfluorododecoxy, perfluorodecoxy, and the like.

The term “carbonyl” (alone or in combination with another term(s)) means—C(O)—, which also may be depicted as:

This term also is intended to encompass a hydrated carbonyl substituent,i.e., —C(OH)₂—.

The term “aminocarbonyl” (alone or in combination with another term(s))means —C(O)—NH₂, which also may be depicted as:

The term “oxy” (alone or in combination with another term(s)) means anether substituent, and may be depicted as —O—.

The term “alkoxy” (alone or in combination with another term(s)) meansan alkylether, i.e., —O-alkyl. Examples of such a substituent includemethoxy (—O—CH₃), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy,sec-butoxy, tert-butoxy, and the like.

The term “alkylcarbonyl” (alone or in combination with another term(s))means —C(O)-alkyl. For example, “ethylcarbonyl” may be depicted as:

The term “aminoalkylcarbonyl” (alone or in combination with anotherterm(s)) means —C(O)-alkyl-NH₂. For example, “aminomethylcarbonyl” maybe depicted as:

The term “alkoxycarbonyl” (alone or in combination with another term(s))means —C(O)—O-alkyl. For example, “ethoxycarbonyl” may be depicted as:

The term “carbocyclylcarbonyl” (alone or in combination with anotherterm(s)) means —C(O)-carbocyclyl. For example, “phenylcarbonyl” may bedepicted as:

Similarly, the term “heterocyclylcarbonyl” (alone or in combination withanother term(s)) means —C(O)-heterocyclyl.

The term “carbocyclylalkylcarbonyl” (alone or in combination withanother term(s)) means —C(O)-alkyl-carbocyclyl. For example,“phenylethylcarbonyl” may be depicted as:

Similarly, the term “heterocyclylalkylcarbonyl” (alone or in combinationwith another term(s)) means —C(O)-alkyl-heterocyclyl.

The term “carbocyclyloxycarbonyl” (alone or in combination with anotherterm(s)) means —C(O)—O-carbocyclyl. For example, “phenyloxycarbonyl” maybe depicted as:

The term “carbocyclylalkoxycarbonyl” (alone or in combination withanother term(s)) means —C(O)—O-alkyl-carbocyclyl. For example,“phenylethoxycarbonyl” may be depicted as:

The term “thio” or “thia” (alone or in combination with another term(s))means a thiaether, i.e., an ether substituent wherein a divalent sulfuratom is in the place of the ether oxygen atom. Such a substituent may bedepicted as —S—. This, for example, “alkyl-thioalkyl” meansalkyl-S-alkyl.

The term “thiol” or “sulfhydryl” (alone or in combination with anotherterm(s)) means a sulfhydryl, and may be depicted as —SH.

The term “(thiocarbonyl)” (alone or in combination with another term(s))means a carbonyl wherein the oxygen atom has been replaced with asulfur. Such a substituent may be depicted as —C(S)—, and also may bedepicted as:

The term “alkyl(thiocarbonyl)” (alone or in combination with anotherterm(s)) means —C(S)-alkyl. For example, “ethyl(thiocarbonyl” may bedepicted as:

The term “alkoxy(thiocarbonyl)” (alone or in combination with anotherterm(s)) means —C(S)O-alkyl. For example, “ethoxy(thiocarbonyl)” may bedepicted as:

The term “carbocyclyl(thiocarbonyl)” (alone or in combination withanother term(s)) means —C(S)-carbocyclyl. For example,“phenyl(thiocarbonyl)” may be depicted as:

Similarly, the term “heterocyclyl(thiocarbonyl)” (alone or incombination with another term(s)) means —C(S)-heterocyclyl.

The term “carbocyclylalkyl(thiocarbonyl)” (alone or in combination withanother tern(s)) means —C(S)alkyl-carbocyclyl. For example,“phenylethyl(thiocarbonyl)” may be depicted as:

Similarly, the term “heterocyclylalkyl(thiocarbonyl)” (alone or incombination with another term(s)) means —C(S)-alkyl-heterocyclyl.

The term “carbocyclyloxy(thiocarbonyl)” (alone or in combination withanother term(s)) means —C(S)—O-carbocyclyl. For example,“phenyloxy(thiocarbonyl)” may be depicted as:

The term “carbocyclylalkoxy(thiocarbonyl)” (alone or in combination withanother term(s)) means —C(S)—O-alkyl-carbocyclyl. For example,“phenylethoxy(thiocarbonyl)” may be depicted as:

The term “sulfonyl” (alone or in combination with another term(s)) means—S(O)₂—, which also may be depicted as:

Thus, for example, “alkyl-sulfonyl-alkyl” means alkyl-S(O)₂-alkyl.

The term “aminosulfonyl” (alone or in combination with another term(s))means —S(O)₂—NH₂, which also may be depicted as:

The term “sulfoxido” (alone or in combination with another term(s))means —S(O)—, which also may be depicted as:

Thus, for example, “alkyl-sulfoxido-alkyl” means alkyl-S(O)-alkyl.

The term “heterocyclyl” (alone or in combination with another tern(s))means a saturated (i.e., “heterocycloalkyl”), partially saturated, orheteroaryl ring structure containing a total of 3 to 14 ring atoms. Atleast one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, orsulfur), with the remaining ring atoms being independently selected fromthe group consisting of carbon, oxygen, nitrogen, and sulfur.

A heterocyclyl may be a single ring, which typically contains from 3 to7 ring atoms, more typically from 3 to 6 ring atoms, and even moretypically 5 to 6 ring atoms. Examples of single-ring heterocyclylsinclude furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (alsoknown as “thiofuranyl”), dihydrothiophenyl, tetrahydrothiophenyl,pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl,isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl,pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl,thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl(including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (also known as“azoximyl”), 1,2,5-oxadiazolyl (also known as “furazanyl”), and1,3,4oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl and1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl,1,2,4dioxazolyl, 1,3,2-dioxazolyl, and 1,3,4dioxazolyl), oxathiolanyl,pyranyl (including 1,2-pyranyl and 1,4-pyranyl), dihydropyranyl,pyridinyl, piperidinyl, diazinyl (including pyridazinyl (also known as“1,2-diazinyl”), pyrimidinyl (also known as “1,3-diazinyl”), andpyrazinyl (also known as “1,4-diazinyl”)), piperazinyl, triazinyl(including s-triazinyl (also known as “1,3,5-triazinyl”), as-triazinyl(also known 1,2,4-triazinyl), and v-triazinyl (also known as“1,2,3-triazinyl”)), oxazinyl (including 1,2,3-oxazinyl, 1,3,2-oxazinyl,1,3,6-oxazinyl (also known as “pentoxazolyl”), 1,2,6-oxazinyl, and1,4-oxazinyl), isoxazinyl (including o-isoxazinyl and p-isoxazinyl),oxazolidinyl, isoxazolidinyl, oxathiazinyl (including 1,2,5-oxathiazinyland 1,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazinyl and1,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl, anddiazepinyl.

A heterocyclyl alternatively may be 2 or 3 rings fused together, suchas, for example, indolizinyl, pyrindinyl, pyranopyrrolyl,4H-quinolizinyl, purinyl, pyridopyridinyl (includingpyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl,pyrido[4,3-b]-pyridinyl, and naphthyridinyl), and pteridinyl. Otherexamples of fused-ring heterocyclyls include benzo-fused heterocyclyls,such as indolyl, isoindolyl, indoleninyl (also known as“pseudoindolyl”), isoindazolyl (also known as “benzpyrazolyl”),benzazinyl (including quinolinyl (also known as “1-benzazinyl”) andisoquinolinyl (also known as “2-benzazinyl”)), phthalazinyl,quinoxalinyl, benzodiazinyl (including cinnolinyl (also known as“1,2-benzodiazinyl”) and quinazolinyl (also known as“1,3-benzodiazinyl”)), benzopyranyl (including chromenyl andisochromenyl), benzothiopyranyl (also known as “thiochromenyl”),benzoxazolyl, indoxazinyl (also known as “benzisoxazolyl”), anthranilyl,benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also knownas “coumaronyl”), isobenzofuranyl, benzothienyl (also known as“benzothiophenyl”, “thionaphthenyl”, or “benzothiofuranyl”),isobenzothienyl (also known as “isobenzothiophenyl”,“isothionaphthenyl”, or “isobenzothiofuranyl”), benzothiazolyl,benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl(including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl,and 3,1,4-benzoxazinyl), benzisoxazinyl (including 1,2-benzisoxazinyland 1,4-benzisoxazinyl), tetrahydroisoquinolinyl, carbazolyl, xanthenyl,and acridinyl.

The term “2-fused-ring” heterocyclyl (alone or in combination withanother term(s)) means a saturated, partially saturated, or heteroarylcontaining 2 fused rings. Examples of 2-fused-ring heterocyclyls includeindolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl,pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl,isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl,benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl,indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl,benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl,benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl,benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl.

The term “heteroaryl” (alone or in combination with another term(s))means an aromatic heterocyclyl containing from 5 to 14 ring atoms. Aheteroaryl may be a single ring or 2 or 3 fused rings. Examples ofheteroaryl substituents include 6-membered ring substituents such aspyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and 1,3,5-, 1,2,4-, and1,2,3-triazinyl; 5-membered ring substituents such as imidazolyl,furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-,1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-memberedfused ring substituents such as benzothiofuranyl, isobenzothiofuranyl,benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-memberedfused rings such as quinolinyl, isoquinolinyl, and 1,4-benzoxazinyl(including cinnolinyl and quinazolinyl).

A carbocyclyl or heterocyclyl can optionally be substituted with, forexample, one or more substituents independently selected from the groupconsisting of halogen, hydroxy, carboxy, keto, alkyl, alkoxy,alkoxyalkyl, alkylcarbonyl (also known as “alkanoyl”), aryl, arylalkyl,arylalkoxy, arylalkoxyalkyl, arylalkoxycarbonyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, andcycloalkylalkoxycarbonyl. More typically, a carbocyclyl or heterocyclylmay optionally be substituted with, for example, one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —C(O)—OH, keto, C₁-C₆-alkyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkylcarbonyl, aryl, aryl-C₁-C₆-alkyl,aryl-C₁-C₆-alkoxy, aryl-C₁-C₆-alkoxy-C₁-C₆-alkyl,aryl-C₁-C₆-alkoxycarbonyl, cycloalkyl, cycloalkyl-C₁-C₆-alkyl,cycloalkyl-C₁-C₆-alkoxy, cycloalkyl-C₁-C₆-alkoxy-C₁-C₆-alkyl, andcycloalkyl-C₁-C₆-alkoxycarbonyl. The alkyl, alkoxy, alkoxyalkyl,alkylcarbonyl, aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, orarylalkoxycarbonyl substituent(s) may further be substituted with, forexample, one or more halogen. The aryls or cycloalkyls are typicallysingle-ring substituents containing from 3 to 6 ring atoms, and moretypically from 5 to 6 ring atoms.

An aryl or heteroaryl can optionally be substituted with, for example,one or more substituents independently selected from the groupconsisting of halogen, —OH, —CN, —NO₂, —SH, —C(O)—OH, amino,aminocarbonyl, aminoalkyl, alkyl, alkylthio, carboxyalkylthio,alkylcarbonyl, alkylcarbonyloxy, alkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylalkoxy, alkoxyalkylthio, alkoxycarbonylalkylthio,carboxyalkoxy, alkoxycarbonylalkoxy, carbocyclyl, carbocyclylalkyl,carbocyclyloxy, carbocyclylthio, carbocyclylalkylthio, carbocyclylamino,carbocyclylalkylamino, carbocyclylcarbonylamino, carbocyclylcarbonyl,carbocyclylalkyl, carbocyclylcarbonyloxy, carbocyclyloxycarbonyl,carbocyclylalkoxycarbonyl, carbocyclyloxyalkoxycarbocyclyl,carbocyclylthioalkylthiocarbocyclyl, carbocyclylthioalkoxycarbocyclyl,carbocyclyloxyalkylthiocarbocyclyl, heterocyclyl, heterocyclylalkyl,heterocyclyloxy, heterocyclylthio, heterocyclylalkylthio,heterocyclylamino, heterocyclylalkylamino, heterocyclylcarbonylamino,heterocyclylcarbonyl, heterocyclylalkylcarbonyl,heterocyclyloxycarbonyl, heterocyclylcarbonyloxy,heterocyclylalkoxycarbonyl, heterocyclyloxyalkoxyheterocyclyl,heterocyclylthioalkylthioheterocyclyl,heterocyclylthioalkoxyheterocyclyl, andheterocyclyloxyalkylthioheterocyclyl. More typically, an aryl orheteroaryl may, for example, optionally be substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —CN, —NO₂, —SH, —C(O)—OH, amino, aminocarbonyl,amino-C₁-C₆-alkyl, C₁-C₆-alkyl, C₁-C₆-alkylthio,carboxy-C₁-C₆-alkylthio, C₁-C₆-alkylcarbonyl, C₁-C₆-alkylcarbonyloxy,C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl,C₁-C₆-alkoxycarbonyl-C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkylthio,C₁-C₆-alkoxycarbonyl-C₁-C₆-alkylthio, carboxy-C₁-C₆-alkoxy,C₁-C6-alkoxycarbonyl-C₁-C₆-alkoxy, aryl, aryl-C₁-C₆-alkyl, aryloxy,arylthio, aryl-C₁-C₆-alkylthio, arylamino, aryl-C₁-C₆-alkylamino,arylcarbonylamino, arylcarbonyl, aryl-C₁-C₆-alkylcarbonyl,arylcarbonyloxy, aryloxycarbonyl, aryl-C₁-C₆-alkoxycarbonyl,aryloxy-C₁-C₆-alkoxyaryl, arylthio-C₁-C₆-alkylthioaryl,arylthio-C₁-C₆-alkoxyaryl, aryloxy-C₁-C₆-alkylthioaryl, cycloalkyl,cycloalkyl-C₁-C₆-alkyl, cycloalkyloxy, cycloalkylthio,cycloalkyl-C₁-C₆-alkylthio, cycloalkylamino,cycloalkyl-C₁-C₆-alkylamino, cycloalkylcarbonylamino,cycloalkylcarbonyl, cycloalkyl-C₁-C₆-alkylcarbonyl,cycloalkylcarbonyloxy, cycloalkyloxycarbonyl,cycloalkyl-C₁-C₆-alkoxycarbonyl, heteroaryl, heteroaryl-C₁-C₆-alkyl,heteroaryloxy, heteroarylthio, heteroaryl-C₁-C₆-alkylthio,heteroarylamino, heteroaryl-C₁-C₆-alkylamino, heteroarylcarbonylamino,heteroarylcarbonyl, heteroaryl-C₁-C₆-alkylcarbonyl,heteroaryloxycarbonyl, heteroarylcarbonyloxy, andheteroaryl-C₁-C₆-alkoxycarbonyl. Here, one or more hydrogen bound to acarbon in any such substituent may, for example, optionally be replacedwith halogen. In addition, the cycloalkyl, aryl, and heteroaryl aretypically single-ring substituents containing 3 to 6 ring atoms, andmore typically 5 or 6 ring atoms.

A prefix attached to a multi-component substituent only applies to thefirst component. To illustrate, the term “alkylcycloalkyl” contains twocomponents: alkyl and cycloalkyl. Thus, the C₁-C₆-prefix onC₁-C₆-alkylcycloalkyl means that the alkyl component of thealkylcycloalkyl contains from 1 to 6 carbon atoms; the C₁-C₆-prefix doesnot describe the cycloalkyl component. To illustrate further, the prefix“halo” on haloalkoxyalkyl indicates that only the alkoxy component ofthe alkoxyalkyl substituent is substituted with one or more halogenradicals. If halogen substitution may alternatively or additionallyoccur on the alkyl component, the substituent would instead be describedas “halogen-substituted alkoxyalkyl” rather than “haloalkoxyalkyl.” Andfinally, if the halogen substitution may only occur on the alkylcomponent, the substituent would instead be described as“alkoxyhaloalkyl.”

If substituents are described as being “independently selected” from agroup, each substituent is selected independent of the other. Eachsubstituent therefore may be identical to or different from the othersubstituent(s).

When words are used to describe a substituent, the rightmost-describedcomponent of the substituent is the component that has the free valence.To illustrate, benzene substituted with methoxyethyl has the followingstructure:

As can be seen, the ethyl is bound to the benzene, and the methoxy isthe component of the substituent that is the component furthest from thebenzene. As further illustration, benzene substituted withcyclohexanylthiobutoxy has the following structure:

When words are used to describe a linking element between two otherelements of a depicted chemical structure, the rightmost-describedcomponent of the substituent is the component that is bound to the leftelement in the depicted structure. To illustrate, if the chemicalstructure is X-L-Y and L is described as methylcyclohexanylethyl, thenthe chemical would be X-ethyl-cyclohexanyl-methyl-Y.

When a chemical formula is used to describe a substituent, the dash onthe left side of the formula indicates the portion of the substituentthat has the free valence. To illustrate, benzene substituted with—C(O)—OH has the following structure:

When a chemical formula is used to describe a linking element betweentwo other elements of a depicted chemical structure, the leftmost dashof the substituent indicates the portion of the substituent that isbound to the left element in the depicted structure. The rightmost dash,on the other hand, indicates the portion of the substituent that isbound to the right element in the depicted structure. To illustrate, ifthe depicted chemical structure is X-L-Y and L is described as—C(O)—N(H)—, then the chemical would be:

The term “pharmaceutically acceptable” is used adjectivally in thispatent to mean that the modified noun is appropriate for use as apharmaceutical product or as a part of a pharmaceutical product.

With reference to the use of the words “comprise” or “comprises” or“comprising” in this patent (including the claims), Applicants note thatunless the context requires otherwise, those words are used on the basisand clear understanding that they are to be interpreted inclusively,rather than exclusively, and that Applicants intend each of those wordsto be so interpreted in construing this patent, including the claimsbelow.

F. Compound Preparation

The detailed examples below illustrate preparation of compounds andsalts of this invention. Other compounds and salts of this invention maybe prepared using the methods illustrated in these examples (eitheralone or in combination with techniques generally known in the art).Such known techniques include, for example, those disclosed in Int'lPubl. No. WO 99/25687 (PCT Patent Application No. PCT/US98/23242published on May 27, 1999) (incorporated herein by reference). Suchknown techniques also include, for example, those disclosed in Int'lPubl. No. WO 00/50396 (PCT Patent Application No. PCT/US00/02518published on Aug. 31, 2000) (incorporated herein by reference). Suchknown techniques further include, for example, those disclosed in Int'lPubl. No. WO 00/69821 (PCT Patent Application No. PCT/US00/06719published on Nov. 23, 2000) (incorporated herein by reference).

EXAMPLES

The following examples are merely illustrative, and not limiting to theremainder of this disclosure in any way.

Example 1 Preparation of4-[[4-(3-aminopropoxy)phenyl]sulfonyl]tetrahydro-2H-pyran-4-carboxylicacid 1,1-dimethylethyl ester, monohydrochloride

Part A. To a solution of t-butylchloroacetate (67 g, 0.44 mol) and4-fluorothiophenol (50 g, 0.40 mol) in N,N-dimethylformamide (1 L) wasadded potassium carbonate (62 g, 0.45 mol), followed bydimethylaminopyridine (2 g, 0.02 mol). The mixture was stirred atambient temperature overnight under nitrogen. Once HPLC showed that thereaction was complete, the mixture was poured into stirring 10% aqueousHCl (1 L) and extracted with ethyl acetate (4×). The combined organiclayers were washed with water (2×), dried over magnesium sulfate,filtered, and concentrated in vacuo to afford 112 g (100⁺% crude yield)of a brown oil. ¹H NMR confirmed the desired sulfide with no disulfideformation. This material was used without further purification.

Part B. To a solution of the product from Part A (approximately 108 g,0.45 mol) in tetrahydrofuran (400 ml) was added water (700 ml), followedby Oxone™ (600 g, 0.98 mol). The reaction mixture was stirred overnight.Once HPLC showed completion, the reaction mixture was filtered to removeexcess Oxone™, and the mother liquor was then extracted with ethylacetate (3×). The combined organic layers were washed with water (2×),dried over magnesium sulfate, filtered, and concentrated in vacuo toafford 78.3 g (64% crude yield) of a yellow oil. Both ¹⁹F and ¹H NMRwere consistent with the desired sulfone with no starting materialremaining. This material was used without further purification.

Part C. To a solution of the product from Part B (78 g, 0.28 mol) inN,N-dimethylacetamide (300 ml) was added potassium carbonate (86 g, 0.62mol). After stirring for 5 min, 2,2′-(dibromoethyl) ether (79 g, 0.34mol) was added, followed by 4-dimethylaminopyridine (1.7 g, 0.014 mol)and tetrabutylammonium bromide (4.5 g, 0.14 mol). The reaction mixturewas stirred overnight via a mechanical stirrer. Once HPLC showedcompletion, the reaction mixture was slowly dumped into stirring 10%aqueous HCl (1 L). The resulting yellow solid was collected and washedwith hexanes to afford 84 g (86%) of a yellow solid. ¹H NMR confirmedthe desired product.

Part D. To a solution of the product from Part C (19.8 g, 57.5 mmol) andt-butyl-N-(3-hydroxypropyl) carbamate (11.1 g, 63.3 mmol) in anhydrousN,N-dimethylformamide (300 mL) at 0° C. was added sodium hydride (2.8 g,69.0 mmol; 60% dispersion in mineral oil). After 18 hr, the reaction wasquenched with water and concentrated in vacuo. The oily residue waspartitioned between ethyl acetate and saturated sodium bicarbonatesolution. The layers were separated, and the organic layer was washedwith brine (3×), dried over sodium sulfate, filtered, and concentratedin vacuo. The oily residue was taken up in acetonitrile and againconcentrated in vacuo. The resulting solid was triturated with diethylether, and 15.3 g (53%) of the pure desired product was collected as awhite powder. ESMS m/z=522 [M+Na]⁺. The filtrate contained 11.6 g ofmaterial which was shown by HPLC to be 55% product. This material couldbe purified by flash chromatography to obtain more material if desired.

Part E. The product from Part D (15.3 g, 30.6 mmol) was taken up in 4NHCl in dioxane (17 mL). After 1 hr, HPLC indicated incomplete reaction,so additional 4N HCl in dioxane (2 mL) was added. After 20 min, thereaction mixture was slowly added to rapidly stirring diethyl ether (400mL). The resulting oily solid was rinsed with more diethyl ether thendissolved in acetonitrile and concentrated in vacuo. 12.3 g (92%) of thedesired hydrochloride salt was obtained as a white solid. ESMS m/z=400[M+H]⁺.

Additional compounds can be prepared by one skilled in the art usingsimilar methods. Examples of such compounds include those having astructure corresponding to generic formula EX-A. Such compounds include,for example, those summarized in Table 1.

TABLE 1 EX-A

Ex # structure n Y¹ Y² ESMS m/z 2

1 CH₃ CH₃ 428 (M + H]⁺ 3

0 CH₃ H 422 [M + Na]⁺ 4

0 H CH₃ 422 [M + Na]⁺ 5

0 H H 408 [M + Na]⁺ 6

2 H H 414 (M + H]⁺

Example 7 Preparation oftetrahydro-4-[[4-[[5-(methoxy-methylamino)-5-oxopentyl]oxy]phenyl]sulfonyl]-N-(tetrahydro-2H-pyran-2-yl)oxy]-2H-pyran-4-carboxamide

Part A. To a solution of 5-benzyloxy-1-pentanol (32.6 g, 168 mmol) inanhydrous N,N-dimethylformamide (150 mL) at 0° C. was added sodiumhydride (7.7 g, 192 mmol, 60% dispersion in mineral oil). After 15 min,the reaction mixture was allowed to warm to 20° C., and then re-cooledto 0° C. A solution of4-[(4-fluorophenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylic acid,1,1-dimethylethyl ester (55.1 g, 160 mmol, as prepared in Example 1,Part C) in anhydrous N,N-dimethylformamide (100 mL) was added, and thecooling bath removed. After 4 hr, the reaction was concentrated invacuo. The oily residue was partitioned between ethyl acetate andsaturated sodium bicarbonate solution. The layers were separated, andthe aqueous layer was back extracted with ethyl acetate (2×). Thecombined extracts were washed with 5% potassium hydrogensulfate, water,and brine (3×); dried over magnesium sulfate; filtered; and concentratedin vacuo. The resulting opaque oil solidified upon standing, and wassubsequently purified by column chromatography using 10-20% ethylacetate/hexanes to afford 67.6 g (81%) of the desired product as a whitesolid. ESMS m/z=541 [M+Na]⁺.

Part B. The product from Part A (20.0 g, 38.6 mmol) was dissolved intetrahydrofuran (80 mL) in a small Fisher/Porter bottle. After purgingwith a stream of nitrogen for 5 min, the reaction was charged with 5%palladium on carbon catalyst (4.0 g, Degussa E101 NO/W, 50% water) andpressurized to roughly 80 psi with hydrogen. After 1.5 hr, hydrogenuptake had ceased and HPLC analysis indicated the reaction was complete.The reaction was filtered through a bed of celite and the filtrate wasconcentrated to yield 17.2 g (100%) of the desired alcohol as a viscousoil. This material was used without further purification.

Part C. The product from Part B (16.5 g, 38.6 mmol) was dissolved inacetonitrile (80 mL). The reaction mixture was treated with carbontetrachloride (80 mL), water (120 mL), then sodium periodate (24.7 g,115.7 mmol), and finally ruthenium trichloride (180 mg, 0.9 mmol). After1 hr, HPLC analysis indicated that the reaction was complete. Thereaction mixture was diluted with methylene chloride (300 mL), and thesolids were removed by gravity filtration. The layers were separated,and the aqueous layer was extracted with methylene chloride (3×). Thecombined organic extracts were dried over magnesium sulfate, filtered,and concentrated in vacuo to yield a blue solid. This was redissolved intetrahydrofuran, slurried with activated carbon, filtered, andconcentrated in vacuo to yield 17.1 g (100%) of an off-white solid.¹HNMR was consistent with the desired product. This material was usedwithout further purification.

Part D. To a solution of the product from Part C (17.1 g, 38.6 mmol) inN,N-dimethylformamide (160 ml) was added 1-hydroxybenzotriazole (7.8 g,57.9 mmol), and then 1-(3-dimethyaminopropyl)-3-ethylcarbodiimidehydrochloride (10.3 g, 54.0 mmol). After 1.5 hr,N,O-dimethylhydroxylamine HCl (11.3 g, 115.7 mmol) and triethylamine(32.2 ml, 231.4 mmol) were added. The reaction mixture was left stirringat ambient temperature overnight. The mixture was concentrated, and theresidue partitioned between ethyl acetate and saturated sodiumbicarbonate solution. The aqueous layer was back extracted with ethylacetate (2×), and the combined organic layers were washed with 5%potassium hydrogensulfate solution, water, and brine (3×), then driedover magnesium sulfate, filtered, and concentrated in vacuo. The crudesolid was purified by column chromatography using 50% ethylacetate/hexanes, and 14.7 g (79%) of the desired weinreb amide wasobtained as an off-white solid. ESMS m/z=508 [M+Na]⁺.

Part E. The product from Part D (6.24 g, 12.85 mmol) was taken up inneat trifluoroacetic acid (50 mL). After 1.5 hr, the trifluoroaceticacid was removed in vacuo at 50° C. to give the free acid as a syrupyoil. ESMS m/z=430 [M+H]⁺. To a solution of this material in anhydrousN,N-dimethylformamide (25 mL) was added 1-hydroxybenzotriazole (2.14 g,15.88 mmol), tetrahydropyranhydroxylamine (4.64 g, 39.72 mmol), andtriethylamine (5.5 mL, 39.72 mmol), followed by1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (3.35 g,15.83 mmol). The reaction mixture was heated at 40° C. for 3.5 hr, andthen cooled to ambient temperature and stirred overnight. The reactionmixture was concentrated in vacuo at 60° C. The residue was taken up inethyl acetate, washed with saturated sodium bicarbonate solution (2×)and brine (3×), dried over sodium sulfate, filtered, and concentrated invacuo to give 8 g of a syrup. The crude material was purified by flashchromatography using 50-100% ethyl acetate/hexanes to give the titlecompound as a white solid. ESMS m/z=529 [M+H]⁺. HRMS calculated forC₂₄H₃₆N₂O₉S: 529.2220 [M+H]⁺. found: 529.2210.

Additional compounds can be prepared by one skilled in the art usingsimilar methods. Examples of such compounds include those having astructure corresponding to generic formula EX-B. Such compounds include,for example, the compound summarized in Table 2.

TABLE 2 EX-B

Ex # structure n Calcd Mass Observed Mass 8

0 518.2172 518.2176 9

1 532.2329 532.2307

Example 10 Preparation oftetrahydro-4-[[4-[3-[(methyl-sulfonyl)oxy]propoxy]phenyl)sulfonyl]-N-[(tetrahydro-2Hpyran-2-yl)oxy]-2H-pyran-4-carboxamide

Part A. To a solution of4-[(4-fluorophenyl)sulfonyl]-tetrahydro-2H-pyran-4-carboxylic acid,1,1-dimethylethyl ester (5.0 g, 14.5 mmol, as prepared in Example 1,Part C) and 3-benzyloxy-1-propanol (2.3 mL, 14.5 mmol) inN,N-dimethylformamide (50 mL) at 0° C. was added NaH (696 mg, 17.4 mmol,60% dispersion in mineral oil). The solution was stirred at ambienttemperature for 5 hr. The reaction was quenched with water, and thenpartitioned between ethyl acetate and water. The organic layer waswashed with water and brine, dried over sodium sulfate, filtered, andconcentrated in vacuo to afford 7.89 g (quantitative yield) of thebenzyl ether as a yellow oil. (ESMS m/z=435 [M−tBu]⁺.

Part B. The benzyl ether of Part A (4.39 g, 8.94 mmol) was hydrolized in1:1 trifluoroacetic acid:methylene chloride (50 mL). The solution wasconcentrated in vacuo to provide 3.69 g (950) of the free acid as acrude white solid. ESMS m/z=452 [M+NH4]⁺. This material was used withoutpurification.

Part C. To a solution of the crude acid of Part B (3.60 g, 8.29 mmol) inN,N-dimethylformamide (40 mL) was added 1-hydroxybenzotriazole (1.34 g,9.95 mmol), triethylamine (3.5 mL, 24.9 mmol), andtetrahydropyranhydroxylamine (2.91 g, 24.9 mmol). After 30 min,1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.23 g,11.6 mmol) was added. The solution was stirred for 18 hr at ambienttemperature. The solution was partitioned between ethyl acetate andsaturated sodium bicarbonate solution. The organic layer was washed withsaturated sodium bicarbonate solution and brine, and then dried oversodium sulfate. Purification by flash chromatography using ethylacetate/hexanes provided 3.71 g (84 0) of the protected hydroxamate as acrude oil. ESMS m/z=551 (M+NH4)⁺. HRMS calculated for C₂₇H₃₅NO₈S NH₄:551.2427 (M+NH4)⁺. Found: 551.2418.

Part D. The benzyl ether of Part C (3.52 g, 6.6 mmol ) was hydrogenatedover 10% palladium/carbon (3.31 g) in methanol with ammonium formate(2.5 g, 39.6 mmol) as the hydrogen source added in 3 portions and heatedat reflux. The solution was filtered through celite and concentrated invacuo to provided 2.89 g (98%) of the alcohol as a colorless oil. ESMSm/z=442 [M−H]⁺. This material was used without purification.

Part E. To a solution of the protected hydroxamate of Part D (2.57 g,5.8 mmol) in methylene chloride (25 mL) was added triethylamine (2.5 mL,18.8 mmol). The solution was cooled to 0° C., and methylsulfonylchloride (1.25 mL, 16.0 mmol) was added. After 18 hr, the reaction waswashed with water, 10% citric acid, 5% sodium bicarbonate solution, andbrine, and then dried over magnesium sulfate. Chromatography (on silica,ethyl acetate/hexanes) provided the title compound as a colorless oil(1.48 g, 49 0). ESMS m/z=544 (M+Na)⁺. HRMS calculated for C₂₁H₃₁NO₁₀S₂NH₄: 539.1733 (M+NH₄)⁺. Found: 539.1709.

Additional compounds can be prepared by one skilled in the art using,similar methods. Examples of such compounds include those having astructure corresponding to generic formula EX-C. Such compounds include,for example, the compounds summarized in Table 3.

TABLE 3 EX-C

Ex # structure n Calcd Mass Observed Mass 11

1 525.1517 525.1561 12

3 558.1444 558.1429 13

4 572.16 572.1583

Example 14 Preparation of(tetrahydro-4-[[4-(2-propenyloxy)phenyl]sulfonyl]-N-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-pyran-4-carboxamide

Part A. To a solution of sodium (8.97 g, 390 mmol) in methanol (1 L) at0° C. were added 4-fluorothiophenol (50 g, 390 mmol) and methylchloroacetate (34.2 mL, 390 mmol). After stirring at ambient temperaturefor 4 hr, the solution was filtered to remove salts, and the filtratewas concentrated in vacuo to provide 75.85 g (970) for the desiredsulfide as a colorless oil.

Part B. To a solution of the product from Part A (75.85 g, 380 mmol) inmethanol (1 L) and water (100 mL) was added Oxone™ (720 g, 1.17 mmol).After 2 hr, the reaction mixture was filtered to remove the excesssalts, and the filtrate was concentrated in vacuo. The resulting residuewas dissolved in ethyl acetate and washed with water, saturated sodiumbicarbonate solution, and brine, and then dried over magnesium sulfate.Concentrating in vacuo provided 82.74 g (94%) of the desired sulfone asa white solid.

Part C. To a solution of the product from Part B (28.5 g, 123 mmol) inN,N-dimethylacetamide (200 mL) were added potassium carbonate (37.3 g,270 mmol), bis-(2-bromoethylether (19.3 mL, 147 mmol),4-dimethylaminopyridine (750 mg, 6 mmol), and tetrabutylammonium bromide(1.98 g, 6 mmol). The resulting solution was stirred at ambienttemperature for 72 hr, and then poured into 1 N HCl (300 mL). Theresulting precipitate was collected by vacuum filtration.Recrystallization using ethyl acetate/hexanes provided 28.74 g (77%) ofthe tetrahydropyran product as a beige solid.

Part D. To a solution of the product from Part C (8.0 g, 26.5 mmol) intetrahydrofuran (250 mL) was added potassium trimethylsilonate (10.2 g,79.5 mmol). After 1.5 hr, the reaction mixture was quenched with water,acidified to pH 2.5, and extracted with ethyl acetate. The organic layerwas washed with brine, dried over sodium sulfate, filtered, andconcentrated in vacuo to afford 5.78 g (76%) of the desired acid salt asa white solid.

Part E. To a solution of the product from Part D (5.4 g, 18.7 mmol) inN,N-dimethylformamide (35 mL) were added 1-hydroxybenzotriazole (3.04 g,22.5 mmol), N-methylmorpholine (6.2 mL, 56.2 mmol),tetrahydropyranhydroxylamine (6.8 g, 58.1 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.0 g, 26.2mmol). After stirring for 3 hr at ambient temperature, the solution wasconcentrated in vacuo, and the residue partitioned between ethyl acetateand water. The organic layer was washed with 5% aqueous potassiumhydrogen sulfate, water, saturated sodium bicarbonate solution, andbrine; dried over sodium sulfate; filtered; and concentrated in vacuo toprovide 6.34 g (87%) of the THP protected hydroxamate as a white solid.

Part F. To a solution of the product from Part E (1.0 g, 2.58 mmol) indimethylsulfoxide (5 mL) was added potassium carbonate (0.89 g, 6.45mmol) and allyl alcohol (0.35 mL, 12.9 mmol). The mixture was heated to110° C. for 72 hr. Additional allyl alcohol (0.88 mL, 13 mmol) andcesium carbonate (2.1 g, 6.45 mmol) were added, and the mixture heatedat 120° C. for 6 hr. After cooling to ambient temperature, the mixturewas diluted with water (50 mL), and the pH adjusted to 8-9 with 1 N HCl.The aqueous layer was extracted with ethyl acetate. The organic layerwas washed brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo. Purification via flash column chromatography with15% ethyl acetate/hexanes yielded 0.67 g of pure title compound as awhite solid. ESMS m/z=426 [M+H]⁺.

Additional compounds can be prepared by one skilled in the art usingsimilar methods. Examples of such compounds include those having astructure corresponding to generic formula EX-D. Such compounds include,for example, the compounds summarized in Table 4.

TABLE 4 EX-D

Ex. # Structure n ESMS m/z 15

2 440 [M + H]⁺ 16

3 454 [M + H]⁺

Example 17 Preparation oftetrahydro-N-hydroxy-4-[[4-[3-[(4-methoxybenzoyl)amino]propoxy]phenyl]sulfonyl]-2H-pyran-4-carboxamide

Part A. To a solution of4-[[4-(3-aminopropoxy)-phenyl]sulfonyl]tetrahydro-2H-pyran-4-carboxylicacid 1,1-dimethylethyl ester, monohydrochloride (507 mg, 1.27 mmol,prepared as in Example 1) in anhydrous N,N-dimethylformamide (5 mL) atambient temperature was added triethylamine (215 uL, 1.54 mmol),followed immediately by panisoyl chloride (260 mg, 1.52 mmol). After 1hr, the reaction mixture was quenched with water (˜2 mL) andconcentrated in vacuo at 60° C. The crude residue was partitionedbetween ethyl acetate and water. The layers wore separated, and theorganic layer was washed with brine (3×), dried over sodium sulfate,filtered, and concentrated in vacuo to give a pale yellow oil. The crudeproduct was partially purified by flash chromatography using 80% ethylacetate/hexanes to provide 225 mg (33%) of the desired acylated productas a clear, colorless oil. ESMS m/z=556 [M+Na]⁺. This material was usedwithout further purification.

Part B. The product from Part A (225 mg, 82% purity by HPLC) was takenup in neat trifluoroacetic acid (1 mL). After 3 hr, the trifluoroaceticacid was removed in vacuo at 50° C. to give the free acid as a colorlessoil. ESMS m/z=478 [M+H]⁺. To a solution of this material in anhydrousN,N dimethylformamide (2 mL) was added 1-hydroxybenzotriazole (72 mg,0.53 mmol), N-methylmorpholine (100 uL, 0.91 mmol) andtetrahydropyranhydroxylamine (78 mg, 0.67 mmol), followed by1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (119 mg, 0.62mmol). The reaction mixture was stirred at ambient temperature for 72hr, and then concentrated in vacuo at 60° C. The residue was partitionedbetween ethyl acetate and water. The layers were separated, and theorganic layer was washed with saturated sodium bicarbonate solution andbrine (2×), dried over sodium sulfate, filtered, and concentrated invacuo to give 255 mg of the desired THP protected hydroxamate as acolorless oil. ESMS m/z=599 [M+Na]³⁰ . HRMS calculated for C₂₈H₃₆N₂O₉S:577.2220 [M+H]⁺. found: 577.2215.

Part C. The product from Part B (255 mg, 88% purity by HPLC) wasdissolved in 4N HCl in dioxane (3 mL) and methanol (300 uL). After 1 hrat ambient temperature, the reaction mixture was poured into rapidlystirring diethyl ether (50 mL). A white solid was collected and driedover P₂O₅ under vacuum. The title compound was obtained as a faint pinksolid. ESMS m/z=493 [M+H]⁺. HRMS calculated for C₂₃H₂₈N₂O₈S: 493.1645[M+H]⁺. found: 493.1636.

Additional compounds (such as those having a structure corresponding togeneric Formula EX-E) can be prepared by one skilled in the art usingsimilar methods with either the t-butyl ester or free acid of4-[[4-(3-aminopropoxy)-phenyl]sulfonyl]-tetrahydro-2H-pyran-4-carboxylicacid 1,1-dimethylethyl ester, monohydrochloride or similarly preparedstarting materials. Also, one may use carboxylic acids as couplingagents in place of acid chlorides using standard peptide couplingconditions for formation of the amide bond.

Example 18 Preparation of1-cyclopropyl-N-hydroxy-4-[[4-[3[(4-methoxybenzoyl)amino]propoxy]phenyl]sulfonyl]-4-piperidinecarboxamide,monohydrochloride

Part A. to a solution of ethyl isonipecotate (15.7 g, 0.1 mol) intetrahydrofuran (100 mL) was added a solution of di-tert-butyldicarbonate (21.8 g, 0.1 mol) in tetrahydrofuran (5 mL) dropwise over 20min. The solution was stirred overnight at ambient temperature andconcentrated in vacuo to yield a light oil. The oil was filtered throughsilica gel using ethyl acetate/hexanes then concentrated in vacuo toafford 26.2 g (100%) of the desired BOC-piperidine as a clear, colorlessoil.

Part B. A solution of 4-fluorothiophenol (50.29 g, 390 mmol) in dimethylsulfoxide (500 mL) was heated to 65° C. for 6 hr. The reaction wasquenched by pouring into wet ice. The resulting solid was collected byvacuum filtration to afford 34.4 g (68.9%) of the desired disulfide as awhite solid.

Part C. To a solution of the product from Part A (16 g, 62 mmol) intetrahydrofuran (300 mL) cooled to −50° C. was added lithiumdiisopropylamide (41.33 mL, 74 mmol). After being at 0° C. for 1.5 hr,the product from Part B (15.77 g, 62 mmol) was added. The reactionmixture was stirred at ambient temperature for 20 hr, and then quenchedby the addition of water. The solution was concentrated in vacuo, andthe resulting residue was partitioned between ethyl acetate and water.The organic layer was washed with 0.5 N KOH, water, and brine.Purification by column chromatography using ethyl acetate/hexanesprovided 18.0 g (75%) of the desired sulfide as an oil.

Part D. To a solution of the product from Part C (16.5 g, 43 mmol) inmethylene chloride (500 mL) cooled to 0° C. was added 3-chloroperbenzoicacid (18.0 g, 86 mmoL). After stirring for 20 hr, the reaction mixturewas diluted with water and extracted with methylene chloride. Theorganic layer was washed with 10% aqueous sodium sulfite, water, andbrine, dried over magnesium sulfate, filtered, and concentrated invacuo. The crude product was purified by column chromatography usingethyl acetate/hexanes to afford 10.7 g (60%) of the desired sulfone as asolid.

Part E. Into a solution of the product from Part D (10 g, 24.0 mmol) inethyl acetate (250 mL) was bubbled HCl gas for 10 min, followed bystirring at ambient temperature for 4 hr. Concentration in vacuoprovided 7.27 g (86%) of the amine hydrochloride salt as a white solid.

Part F. To a solution of the product from Part E (10.0 g, 28.4 mmol) inmethanol (100 mL) was added acetic acid (16.2 mL, 284 mmol), powdered 4Amolecular sieves (9.1 g), and [(1-ethoxycyclopropyl)oxyl trimethylsilane (17.1 mL, 85.2 mmol). Sodium cyanoborohydride (4,82 g, 76.7 mmol)was then added slowly. The reaction was heated at reflux with vigorousstirring for 4.5 hr. The reaction mixture was cooled to roomtemperature, filtered through celite, and concentrated in vacuo. Theresidue was partitioned between ethyl acetate and saturated sodiumbicarbonate solution. The organic layer was washed with saturated sodiumbicarbonate solution (3×) and brine, dried over magnesium sulfate,filtered, and concentrated in vacuo. The crude material crystallizedupon standing providing 10.9 g (100%) of the alkylated amine compound asa pale yellow oily crystal. ESMS m/z=356 (M+H)⁺. This material was usedwithout purification.

Part G. The product from Part F (28.4 mmol) was hydrolized intetrahydrofuran (65 mL) with LiOH (3.58 g, 85.2 mmol) in 35 mL of waterat 60° C. over 3 days. The solution was concentrated in vacuo, dilutedwith water, and washed with diethyl ether. The aqueous layer wasacidified with 1N HCl to a pH of ˜4.5, causing a white precipitate toform. The solid was collected by filtration, washed with water, andwashed with ethyl acetate. After drying over silica on a high vacuum,8.06 g (78.2%) of the acid was obtained as a crude white solid. ESMSm/z=328 (M+H)+. HRMS calculated for C₁₅H₁₈NO₄SF: 328.1019 (M+H)⁺. found:328.1014. This material was used without purification.

Part H. To a solution of the crude acid of Part G (7.92 g, 21.8 mmol) inN,N-dimethylformamide (48 mL) was added N-methylmorpholine (12.0 mL, 109mmol) and PyBOP (12.5 g, 24.0 mmol). After stirring 15 min,tetrahydropyranhydroxylamine (3.07 g, 26.2 mmol) was added. The solutionwas stirred for 22 hr at ambient temperature. The solution was dilutedwith water (240 mL) and extracted with ethyl acetate (3×). The combinedorganics were washed with saturated aqueous sodium bicarbonate solution(2×) and brine, dried over sodium sulfate, filtered, and concentrated invacuo to a foamy oil. The crude material was filtered through a silicaplug using 1% Et₃N in ethyl acetate/hexanes to afford 7.12 g (76.60) ofthe protected hydroxamate as a foamy oil. ESMS m/z=427 (M+H)⁺. HRMScalculated for C₂₀H₂₇N₂O₅SF: 427.1703 (M+H)⁺. Found: 427.1693.

Part I. To a solution of 3-(dibenzylamino)-1-propanol (4.3 g, 16.88mmol) in anhydrous N,N-dimethylformamide (35 mL) was added sodiumhydride (1.3 g, 32.35 mmol; 60% dispersion in mineral oil). The reactionmixture was stirred for 15 min, then cooled to 0° C. in an ice bath andtreated with a solution of the product from Part H (6.0 g, 14.07 mmol)in anhydrous N,N-dimethylformamide (15 mL). After the addition wascompleted, the ice bath was removed and the reaction was allowed to stirat ambient temperature for 18 hr. The reaction was quenched with waterand concentrated in vacuo. The oily residue was partitioned betweenethyl acetate and saturated sodium bicarbonate solution. The layers wereseparated and the aqueous layer was extracted with ethyl acetate (3×).The organic extracts were combined and washed with brine (3×), driedover sodium sulfate, filtered, and concentrated in vacuo. The crudeyellow solid was re-crystallized from hot acetonitrile. 6.5 g (70%) ofthe pure desired product was collected as a white powder. ESMS m/z=662[M+H]⁺.

Part J. The product from Part I (1.0 g, 1.51 mmol) and glacial aceticacid (0.2 g, 3.02 mmol) were slurried in methanol (15 mL) in a smallFisher/Porter bottle. After purging with a stream of nitrogen for 5 min,the reaction was charged with 20% palladium on carbon catalyst (0.5 g,Degussa E169X/W, 50% water) and pressurized to 50 psi with hydrogen.After 5 hr, hydrogen uptake had ceased, and HPLC analysis indicated thereaction was complete. The reaction was filtered through a bed ofcelite, and the filtrate was concentrated to yield 0.8 g (1000) of thedesired mono-acetate salt as a dry, white foam. ESMS m/z=481 [M+H]⁺.

Part K. To a solution of the product from Part J (0.7 g, 1.06 mmol) inanhydrous methylene chloride (11 mL) at ambient temperature was addedtriethylamine (0.73 mL, 6.35 mmol), followed by p-anisoyl chloride (0.3g, 1.59 mmol). After 10 min, HPLC analysis showed the reaction to becomplete. The reaction mixture was concentrated in vacuo, and theresidue was partitioned between ethyl acetate and saturated sodiumbicarbonate solution. The layers were separated, and the aqueous layerextracted with ethyl acetate (3×). The organic extracts were combinedand washed with brine (3×), dried over sodium sulfate, filtered, andconcentrated in vacuo to yield a tan foam. The crude product waspurified by flash chromatography using 60-100% [5% (2M ammonia inmethanol) ethyl acetate]hexanes to yield 0.2 g (34%) of the desiredproduct as a dry white foam. ESMS m/z=616 [M+H]⁺.

Part L. The product from Part K (0.2 g, 0.34 mmol) was slurried in 4NHCl in dioxane (2 mL). After 5 min, methanol (0.2 mL) was added. Afterstirring for 10 min at ambient temperature, the reaction mixture waspoured into rapidly stirring diethyl ether (50 mL). A white solid wascollected and dried under vacuum. The title compound (as the HCl salt)was obtained as an off-white solid. ESMS m/z=532 [M+H]⁺. HRMS calculatedfor C₂₆H₃₃N₃O₇S: 532.2117 [M+H]+. found: 532.2098.

Additional compounds can be prepared by one skilled in the art usingsimilar methods. Examples of such compounds include those having astructure corresponding to generic formula EX-F.

Example 19 Preparation of4-[[4-[3-[[4-(dimethylamino)benzoyl]methylamino]propoxyl]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A. To a solution of4-[[4-[3-[[4(dimethylamino)-benzoyl]amino]propoxy]phenyl]sulfonyl]tetrahydro-2H-pyran-4-carboxylicacid, 1,1-dimethylethyl ester (prepared as in Example 17) in anhydrousN,N-dimethylformamide (3 mL) was added iodomethane (61 uL, 0.98 mmol),followed by sodium hydride (24 mg, 0.59 mmol; 60% dispersion in mineraloil). After 1 hr the reaction mixture was quenched with water, washedwith brine (3×), dried over sodium sulfate, filtered, and concentratedin vacuo to yield the desired N-methylated product as a sticky solid.ESMS m/z=561 [M+H]⁺. HRMS calculated for C₂₉H₄₀N₃O₇S: 561.2634 [M+H]⁺.found: 561.2628.

Part B. The product from Part A (400 mg, 0.71 mmol) was taken up in neattrifluoroacetic acid (1 mL). After 1 hr, the trifluoroacetic acid wasremoved in vacuo at 60° C. to give the free acid as a sticky solid. ESMSm/z=505 [M+H]⁺. To a solution of this material in anhydrous N,Ndimethylformamide (5 mL) was added 1-hydroxybenzotriazole (113 mg, 0.83mmol), tetrahydropyranhydroxylamine (246 mg, 2.10 mmol), andtriethylamine (390 uL, 2.8 mmol), followed by1-(3dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (188 mg, 0.98mmol). The reaction mixture was heated to 40° C. for 4 hr, and thencooled to ambient temperature. The reaction mixture was diluted withethyl acetate, washed with saturated sodium bicarbonate solution (2×)and brine (4×), dried over sodium sulfate, filtered, and concentrated invacuo. The crude product was de-protected and simultaneously purified byreverse phase HPLC to give 59 mg of the title compound as an off-whitesolid. ESMS m/z=520 [M+H]⁺. HRMS calculated for C₂₅H₃₃N₃O₇S: 520.2117[M+H]⁺. found: 520.2120.

Additional compounds can be prepared by one skilled in the art usingsimilar methods. Examples of such compounds include those having astructure corresponding to generic formula EX-G.

Example 20 Preparation of4-[[4-[[5-[[4-(dimethylamino)phenyl]amino]-5-oxopentyl]oxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide,monohydrochloride

Part A. To a solution of4-[[4-(4-carboxybutoxy)phenyl]sulfonyl]tetrahydro-2H-pyran-4-carboxylicacid, 1,1-dimethylethyl ester (446 mg, 0.91 mmol, prepared as in Example7) in anhydrous N,N-dimethylformamide (6 mL) was added1-hydroxybenzotriazole (150 mg, 1.11 mmol), triethylamine (400 uL, 2.87mmol), N,N-dimethyl-1,4-phenylenediamine (188 mg, 1.38 mmol), andfinally 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (300mg, 1.56 mmol). The reaction mixture was stirred at ambient temperaturefor 18 hr, and then concentrated in vacuo at 60° C. The residue waspartitioned between ethyl acetate and saturated sodium bicarbonatesolution. The organic layer was washed with brine (2×), dried oversodium sulfate, filtered, and concentrated in vacuo to give the desiredamide. ESMS m/z=561 [M+H]⁺. This material was taken up in neattrifluoroacetic acid (5 mL). After 3 hr the trifluoroacetic acid wasremoved in vacuo at 60° C. to give the free acid. ESMS m/z=505 [M+H]⁺.To a solution of this material in anhydrous N,N-dimethylformamide (5 mL)was added 1-hydroxybenzotriazole (148 mg, 1.10 mmol), triethylamine (400uL, 2.87 mmol), and tetrahydropyranhydroxylamine (320 mg, 2.73 mmol),followed by 1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride(262 mg, 1.37 mmol). The reaction mixture was stirred at ambienttemperature overnight, and then partitioned between ethyl acetate andsaturated sodium bicarbonate solution. The organic layer was washed withbrine (3×), dried over sodium sulfate, filtered, and concentrated invacuo. The crude material was purified by flash chromatography using 80%ethyl acetate/hexanes as eluant to afford the desired THP hydroxamate.ESMS m/z=604 [M+H]⁺. HRMS calculated for C₃₀H₄₁N₃O₈S: 604.2693 [M+H]⁺.found: 604.2709.

Part B. The product from Part A was dissolved in 4N HCl in dioxane (5mL) and methanol (500 uL). After 3 hr at ambient temperature thereaction mixture was poured into rapidly stirring diethyl ether (50 mL).A purplish-pink solid was collected and subsequently purified by reversephase HPLC. The title compound was obtained as a faint pink solid 131 mg(28% from the starting acid in part A). ESMS m/z=520 [M+H]⁺. HRMScalculated for C₂₅H₃₃N₃O₇SHCl: 520.2117 [M+H]⁺. found: 520.2127.

Additional compounds can be prepared by one skilled in the art usingsimilar methods. Examples of such compounds include those having astructure corresponding to generic formula EX-H.

Example 21 Preparation of4-[[4-[3-(1,3-dibydro1,3-dioxo2H-isoindol-2-yl)propoxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A. To a solution of4-[(4-fluorophenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylic acid,1,1-methylethyl ester (6.7 g, 19 mmol, as prepared in Example 1, Part C)in anhydrous N,N-dimethylformamide (40 ml) at ambient temperature wasadded N-(3-hydroxypropyl)phthalimide (4 g, 19 mmol), followedimmediately by NaH (700 mg, 20 mmol, 60% dispersion in mineral oil).After 1.5 hr, HPLC showed less than 1% of the starting electrophile. Thereaction mixture was quenched with water (60 ml). The cloudy mixture wasextracted with ethyl acetate (2×100 ml). The organic layers werecombined, washed with brine (1×200 ml), dried over sodium sulfate,filtered, and concentrated in vacuo to give a tan, viscous oil thatcrystallized from methanol (3.2 g, 52%). ESMS m/z=489 (M+H]⁺. Thismaterial was used without further purification.

Part B. The product from Part A (3 g, 6 mmol) was dissolved in methylenechloride (304 ml) and trifluoroacetic acid (6 ml). After 12 hr, themixture was concentrated in vacuo, and the residue was triturated withdiethyl ether to form a solid which was collected and dried to affordthe carboxylic acid as a beige solid (3 g, 90%). ESMS m/z=474 [M+H]⁺.This material was used without further purification.

Part C. To a solution of the product from Part B (3 g, 6.2 mmol) inanhydrous N,N-dimethylformamide (25 ml) was added triethylamine (2 ml,18 mmol), followed by tetrahydropyranhydroxylamine (1 g, 8 mmol),1-hydroxybenzotriazole (0.5 g, 3 mmol), and1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (2 g, 8mmol). The reaction mixture was heated at 40° C. for 0.5 hr. Thereaction was monitored by RPHPLC. After 2 hr, the mixture wasconcentrated in vacuo, the residue was flooded with water, and theproduct separated as a solid. The solid was filtered, and was ofsufficient purity to carry on to the next step. Mass spectral data andNMR were consistent with the desired product.

Part D. The solid from Part C (3 g) was slurried in methanol (1 mL) anddiethyl ether (30 ml). To this was added 4N HCl in dioxane (10 ml) andstirred for 2 hr. RPHPLC showed complete reaction. The reaction mixturewas concentrated by half, diethyl ether (100 mL) was added, and thewhite solid (1.5 g, 70% yield) filtered and dried under vacuum. ¹H NMRwas consistent with the desired product ESMS m/z C₂₃H₂₄N₂O₈S=489 [M+H]⁺.HRMS calculated for C₂₃H₂₄N₂O₈S: 489.1332 [M+H]⁺. found: 489.1298.

Example 22 Preparation of4-[[4-[3-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)propoxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A. To a solution of4-[(4-fluorophenyl)-sulfonyl]tetrahydro-2H-pyran-4-carboxylic acid,1,1-dimethylethyl ester (5.2 g, 15 mmol, as prepared in Example 1, PartC) in dimethyl sulfoxide (40 ml) at ambient temperature was addedN-(3-hydroxypropyl)phthalide (3 g, 15 mmol, prepared according toJ.Med.Chem., 146-157 (1996)), followed by cessium carbonate (12 g,45mmol). After 15 hr at 80° C., HPLC indicated complete reaction. Thereaction mixture was quenched with water (60 ml). The cloudy mixture wasextracted with ethyl acetate (2×100 ml). The organic layers werecombined, washed with brine (1×200 ml), dried over sodium sulfate,filtered, and concentrated in vacuo to give a tan, viscous oil thatcrystallized from methanol (7 g, 720). ESMS m/z=516 (M+H]⁺, NMR wasconsistent with desired product. This material was used without furtherpurification.

Part B. The product from Part A (3 g, 6 mmol) was dissolved in methylenechloride (300 ml) and trifluoroacetic acid (6 ml). After 12 hr ofstirring, the mixture was concentrated in vacuo and the residue wastriturated with diethyl ether to form a solid which was collected anddried to afford the carboxylic acid as a beige solid (3 g, 91%). ESMSm/z=474 [M+H]⁺. This material was used without further purification.

Part C. To a solution of the product from Part B (3 g, 6.2 mmol) inN,N-dimethylformamide (25 ml) was added triethylamine (2 ml, 18 mmol),followed by tetrahydropyranhydroxylamine (1.2 g, 8 mmol),1-hydroxybenzotriazole (0.5 g, 3 mmol), and1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 g, 8mmol). The reaction mixture was heated at 40° C. for 0.5 hr. Thereaction was monitored by RPHPLC. After completion the mixture wasconcentrated and the residue was flooded with water. The resulting solidwas filtered, and was of sufficient purity to carry on to the next step.Mass spectral data and NMR were consistent with the desired product.

Part D. The solid from Part C (3 g) was slurried in methanol (1 mL) anddiethyl ether (30 ml). To this was added 4N HCl in dioxane (10 ml) andstirred for 2 hr. RPHPLC showed complete reaction. The reaction mixturewas concentrated by half, diethyl ether (100 mL) was added, and thewhite solid (2.5 g, 90% yield) filtered and dried under vacuum. ¹H NMRwas consistent with the desired product. HRMS calculated forC₂₃H₂₆N₂O₇S: 475.1525 [M+H]⁺. found: 475.1510.

Example 23 Preparation of4-[[4-[[4E)5-[-4-(dimethylamino)phenyl]-4-pentenyl]oxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamideand4-[[4-[[4Z)-5-[-4-(dimethyl-amino)phenyl]-4-pentenyl]oxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide,monohydrochloride

Part A To a solution of4-[(4-fluorophenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylic acid,1,1-di-methylethyl ester (10.0 g, 29.0 mmol, as prepared in Example 1,Part C) in N,N-dimethylformamide (60 ml) at ambient temperature wasadded 4-penten-1-ol (3.1 ml, 30.0 mmol), followed immediately by NaH(1.4 g, 34.8 mmol, 60% dispersion in mineral oil). After 1.5 hr, HPLCshowed less than 1% of the starting material. The reaction mixture wasquenched with water (60 ml). The cloudy mixture was extracted with ethylacetate (3×300 ml). The organic layers were combined; washed with 5%potassium hydrogensulfate (1×200 ml), saturated sodium bicarbonatesolution (1×200 ml), water (1×200 ml), and brine (1×200 ml); dried oversodium sulfate; filtered; and concentrated in vacuo to give a tan oil.The crude product was partially purified by flash chromatography using15% ethylacetate/hexanes to provide 11.7 g (98%) of the desired etherproduct as a clear, colorless oil. ESMS m/z=433 [M+Na]⁺. This materialwas used without further purification.

Part B. To a solution of the product from Part A (2.0 g, 4.9 mmol) inN,N-dimethylformamide (3 ml) was added 4-bromo-N,N-dimethylaniline (1.2g, 5.8 mmol), followed by triethylamine (1.4 ml, 9.8 mmol),tri-ortho-tolylphosphine (34 mg, 0.10 mmol), and palladium(II) acetate(12 mg, 0.05 mmol). The reaction was heated at 100° C. for 12 hr. Thereaction was cooled and diluted with water (5 ml). The aqueous wasextracted with ethyl acetate (3×15 ml). The organic extracts were driedover sodium sulfate, filtered, and concentrated in vacuo to afford ablack oil (3.2 g). The black crude product was partially purified byflash chromatography using 5% ethyl acetate/hexanes to provide 1.2 g ofthe olefinic product as a tan oil (45% yield, trans:cis, 3:1). ESMSm/z=552 [M+Na]⁺. This material was used without further purification.

Part C. The product from Part B (1.2 g, 2.3 mmol) was dissolved inmethylene chloride (4 ml) and trifluoroacetic acid (4 ml). After 1 hr ofstirring, the mixture was concentrated and the residue was trituratedwith diethyl ether to form a solid which was collected and dried toafford the carboxylic acid-TFA salt as a beige solid (0.73 g, 510). ESMSm/z=474 [M+H]⁺. This material was used without further purification.

Part D. To a solution of the product from Part C (0.73 g, 1.2 mmol) inN,N-dimethylformamide (4 ml) was added triethylamine (0.9 ml, 6.2 mmol),followed by tetrahydropyranhydroxylamine (0.28 g, 2.4 mmol),1-hydroxybenzotriazole (0.19 g, 1.4 mmol), and1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (0.32 g, 1.8mmol). The reaction mixture was heated at 40° C. for 24 hr. The mixturewas concentrated and the residue was purified via reverse phasechromatography (C₁₈, acetonitrile/water/TFA). Fractions (10 ml) werecollected to separate the isomers. While analyzing, the aqueous TFAmixtures de-protected the product affording the hydroxamic acid finalproducts.4-[[4-[[4E)-5-[-4-(dimethylamino)phenyl]-4-pentenyl]oxy]phenyl]sulfonyl]-tetrahydro-N-hydroxy-2H-pyran-4-carboxamide,(98% trans isomer by HPLC, 0.12 g, 17% yield). HRMS calculated forC₂₃H₂₈N₂O₈S: 489.2059 [M+H]⁺. found: 489.2067. ¹H NMR confirmed transisomerization (Job=15.9 Hz).4-[[4-[[4Z)-5-[-4-(dimethyl-amino)phenyl]-4-pentenyl]oxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide,monohydrochloride, (79% cis/17% trans by HPLC, 15 mg tan solid, 2%yield). HRMS calculated for C₂₅H₃₂N₂O₆S: 489.2059 [M+H]⁺. found:489.2067.

Example 24 Preparation oftetrahydro-N-hydroxy-4-[[4-[[5(4-methoxyphenyl)-5-oxopentyl]oxy]phenyl]sulfonyl]-2H-pyran-4-carboxamide

Part A. To a mixture of magnesium turnings (344 mg, 14.18 mmol) etchedwith iodine in anhydrous tetrahydrofuran (4 mL) at reflux was added4-bromoanisole (1.2 mL, 9.45 mmol) dropwise over 10 min. The reactionmixture was heated at reflux for 45 min, and then cooled to ambienttemperature. The prepared grignard reagent was added to a mixture oftetrahydro-4-[[4-[[5-(methoxymethylamino)-5-oxopentyl]oxy]phenyl]sulfonyl]-N-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-pyran-4-carboxamide(1.0 g, 1.9 mmol, as prepared in Example 7) in anhydrous tetrahydrofuran(10 mL) at 0° C. The reaction mixture was warmed to ambient temperatureand left stirring overnight. The reaction was quenched with saturatedammonium chloride, and then partitioned between ethyl acetate and water.The layers were separated, and the organic layer was washed with brine,dried over sodium sulfate, filtered, and concentrated in vacuo. Thecrude material was purified by flash chromatography using 50-100% ethylacetate/hexanes to afford 320 mg (29%) of the desired ketone as a whitepowder. ESMS m/z=593 [M+NH₄]⁺. HRMS calculated for C₂₉H₃₇NO₉S: 593.2533[M+NH₄]⁺. found: 593.2555.

Part B. The product from Part A (300 mg, 0.52 mmol) was dissolved in 4NHCl in dioxane (3 mL) and methanol (300 uL). After 10 min at ambienttemperature, the reaction mixture was poured into hexanes (75 mL), andthe product precipitated out as an oil. The solvent was decanted andadditional hexanes was added. The resulting solid was triturated withdiethyl ether, and the title compound was obtained as an off-whitesolid. ESMS m/z=492 [M+H]⁺. HRMS calculated for C₂₄H₂₉NO₈S: 492.1692[M+H]⁺. found: 492.1713.

Additional compounds can be prepared by one skilled in the art usingsimilar methods with either the t-butyl ester, THP protectedhydroxamate, or resin bound hydroxamate of the weinreb amide. Examplesof such compounds include those having a structure corresponding togeneric formula EX-I.

Example 25 Preparation oftetrahydro-N-hydroxy-4-[[4-[[5-(hydroxyimino)-5-(4-methoxyphenyl)pentyl]oxy]phenyl]-sulfonyl]-2H-pyran-4-carboxamide

Part A. To a mixture of magnesium turnings (1.2 g, 49.4 mmol) etchedwith iodine in anhydrous tetrahydrofuran (4 mL) at reflux was added1-bromo-2,4-dimethyoxybenzene (6.0 mL, 41.7 mmol) dropwise over 10 min.The reaction mixture was heated at reflux for 30 min, and then cooled toambient temperature. The prepared grignard reagent was added to amixture oftetrahydro-4-[[4-[3-(methoxymethyl-amino)-3-oxopropoxy]phenyl]sulfonyl]-2H-pyran-4-carboxylicacid, 1,1-dimethylethyl ester (1.0 g, 1.9 mmol, prepared as in Example7) in anhydrous THF (10 mL) at 0° C. The reaction mixture was warmed toambient temperature, and, after 2 hr, was quenched with saturatedammonium chloride, and then partitioned between ethyl acetate and water.The layers were separated, and the organic layer was washed with brine,dried over sodium sulfate, filtered, and concentrated in vacuo. Thecrude material was covered with diethylether. The resulting green solidwas triturated with diethyl ether. The final solid was collected toafford 2.2 g (94%) of the desired ketone as a pale green powder. ESMSm/z=585 [M+Na]⁺. HRMS calculated for C₂₉H₃₈NO₉S : 563.2315 [M+H]⁺.found: 563.2319.

Part B. The product from Part A (2.2 g, 3.91 mmol) was taken up in neattrifluoroacetic acid (6 mL). After 2 hr, the trifluoroacetic acid wasremoved in vacuo at 50° C. to give the free acid as a purple oil. ESMSm/z=507 [M+H]⁺. To a solution of this material in anhydrousN,N-dimethylformamide (20 mL) was added 1-hydroxybenzotriazole (670 mg,4.96 mmol), triethylamine (1.8 mL, 12.91 mmol),tetrahydropyranhydroxylamine (1.48 g, 12.63 mmol), and1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (1.13 g, 5.89mmol). After 16 hr, the reaction mixture was concentrated in vacuo at60° C. The crude material was partitioned between ethyl acetate andsaturated sodium bicarbonate solution. The organic layer was washed withbrine (2×), dried over sodium sulfate, filtered, and concentrated invacuo to yield a yellow oil. Purification by flash chromatography using80% ethyl acetate/hexanes afforded a mixture of THP hydroxamate/THPoxime (78%) and THP hydroxamate ketone (12%). ESMS m/z=621 [M+H]⁺andESMS m/z=628 [M+H]⁺respectively. These products were not separated, andinstead were carried forward as a mixture.

Part C. The product from Part B (540 mg, 0.77 mmol) was dissolved in 4NHCl in dioxane (5 mL) and methanol (500 uL). After 2 hr at ambienttemperature the reaction mixture was poured into rapidly stirringdiethyl ether. A pale pinkish/purple solid was collected and purified byreverse phase HPLC. The title compound was obtained as a white solid.ESMS m/z=537 [M+H]⁺. HRMS calculated for C₂₅H₃₂N₂O₉S: 537.1907 [M+H]⁺.found: 537.1921.

Example 26 Preparation oftetrahydro-N-hydroxy-4-[[4-[[5-(4-methyloxyphenyl)-4-methyl-5-oxopentyl]oxy]phenyl]sulfonyl]-2H-pyran-4-carboxamide

Part A. To a solution oftetrahydro-4-[[4-[[5-(4methoxyphenyl)-5-oxopentyl]oxy]phenyl]sulfonyl]-2H-pyran-4-carboxylicacid, 1,1-dimethylethyl ester (532 mg, 1.0 mmol, prepared as in Example24) and iodomethane (623 mg, 4.4 mmol) in 5 ml N,N-dimethylformamide wasadded sodium hydride (125 mg, 3.1 mmol, 60% dispersion in mineral oil).The reaction was stirred 40 min then quenched with 1N HCl_(aq). Thereaction mixture was partitioned between ethyl acetate and 5% aqueouspotassium hydrogensulfate. The organic phase was dried over sodiumsulfate, filtered, and concentrated in vacuo to give a crude oil.Purification by flash chromatography using 40% ethyl acetate/hexanesafforded 370 mg (68% yield) of the desired monomethyl ketoester. ESMSm/z=547 [M+H]⁺.

Part B. The product from Part A (370 mg, 0.68 mmol) was taken up in neattrifluoroacetic acid. After 45 min, HPLC analysis indicated that thereaction was complete. The trifluoroacetic acid was removed in vacuo,and the residue chased with acetonitrile (2×10 ml), and then vacuumdried to yield 335 mg of the free acid. ESMS m/z=491 [M+H]⁺. To asolution of this material in anhydrous N,N-dimethylformamide (4 mL) wasadded 1-hydroxybenzotriazole (138 mg, 0.68 mmol) and1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (150 mg, 0.78mmol), followed by triethylamine (190 uL, 1.36 mmol) andtetrahydropyranhydroxylamine (160 mg, 1.37 mmol). After 16 hr, thereaction mixture was partitioned between ethyl acetate and 5% aqueouspotassium hydrogensulfate. The combined organic extracts were washedwith brine, dried over sodium sulfate, filtered, and concentrated invacuo to a crude oil. Purification by flash chromatography using 60%ethyl acetate/hexanes as eluant afforded 270 mg (67%) of the desired THPprotected hydroxamate. ESMS m/z=590 [M+H]⁺.

Part C. The product from Part B (270 mg, 0.46 mmol) was dissolved in 4NHCl in dioxane (2 mL) and methanol (500 uL). After 15 min at ambienttemperature, the reaction mixture was partitioned between ethyl acetateand water. The organic layer was dried over sodium sulfate, filtered,and concentrated in vacuo to yield 200 mg (86%) of the title compound.ESMS m/z=406 [M+H]⁺. HRMS calculated for C₂₅H₃₁NO₈S 506.1849 [M+H]⁺.found: 506.1828.

Example 27 Preparation of4-[[4-[[(4Z)-5-cyano-5-(4-methoxyphenyl)-4-pentenyl]oxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A. To a solution oftetrahydro-4-[[4-[[5-(4-methoxyphenyl)-5-oxopentyl]oxy]phenyl]sulfonyl]-2H-pyran-4-carboxylicacid, 1,1-dimethylethyl ester (1.0 g, 1.9 mmol, prepared as in Example24) in 15 ml methylene chloride was added trimethylsilyl cyanide (300uL, 2.2 mmol) and zinc iodide (660 mg, 2.1 mmol). The reaction wasstirred at ambient temperature for 3 hr, and then concentrated in vacuo.The residue was partitioned between ethyl acetate and 1 N HCl_(aq). Theorganic layer was dried over sodium sulfate, filtered, and concentratedin vacuo. The crude product was purified by flash chromatography using25% ethyl acetate/hexanes to afford 950 mg (81%) of the silylatedcyanohydrin. This material was taken up in trifluoroacetic acid (15 mL).The dark red solution showed various peaks by HPLC analysis over thefirst 40 min. After 1 hr, HPLC analysis indicated 1 new peak at 93%. Thereaction mixture was concentrated in vacuo and chased with acetonitrile(2×10 ml). The crude solid was dissolved in methanol and added to 40 mldiethyl ether. The resulting white solid was filtered and dried to yield630 mg of the free acid/cyano olefin. ESMS m/z=486 [M+H]⁺.

Part B. To a solution of the product from Part A (630 mg, 1.3 mmol) inanhydrous N,N-dimethylformamide (15 mL) was added 1-hydroxybenzotriazole(285 mg, 2.1 mmol) and 1-(3-dimethyaminopropyl)-3-ethylcarbodiimidehydrochloride (285 mg, 1.5 mmol), followed by N-methylmorpholine (545uL, 5.0 mmol) and tetrahydropyranhydroxylamine (456 mg, 3.9 mmol). After20 hr, the reaction mixture was concentrated in vacuo, and thenpartitioned between ethyl acetate and 5% aqueous potassiumhydrogensulfate. The combined organic extracts were washed with brine,dried over sodium sulfate, filtered, and concentrated in vacuo.Purification by flash chromatography using 80% ethyl acetate/hexanes toafford 530 mg (70%) of the desired THP protected hydroxamate. ESMSm/z=585 [M+H]⁺.

Part C. The product from Part B (530 mg, 0.91 mmol) was dissolved in 4NHCl in dioxane (5 mL) and methanol (1 mL). After 15 min at ambienttemperature, the reaction mixture was partitioned between ethyl acetateand water. The organic layer was dried over sodium sulfate, filtered,and concentrated in vacuo to yield 360 mg of the desired hydroxamicacid. Purification by reverse phase HPLC afforded 270 mg (59%) of thetitle compound. ESMS m/z=504 [M+H]⁺. HRMS calculated for C₂₅H₂₈N₂O₇S:501.1695 [M+H]⁺. found: 501.1689.

Example 28 Preparation oftetrahydro-N-hydroxy-4-[[4[[(4E)-5-(4-methoxyphenyl)-4-hexenyl]oxy]phenyl]sulfonyl]-2H-pyran-4-carboxamide

Part A. To a cooled (0° C.) solution of4-[(4-{[5-(4-methoxyphenyl)-5-oxopentyl]oxy}phenylsulfonyl]-N-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-4-carboxamide(0.2 g, 0.4 mmol, as prepared in Example 24) in tetrahydrofuran (2 ml)was added a 3.0 M solution of methylmagnesium bromide (1.2 ml, 3.6mmol). The ice bath was removed, and the reaction stirred for 2 hr atroom temperature. HPLC showed less than 1% of the ketone startingmaterial. The reaction mixture was diluted with ethyl acetate and washedwith saturated ammonium chloride solution, water, and brine. Afterdrying over sodium sulfate and filtering, the organic layer wasconcentrated in vacuo to afford 0.25 g (100%) of a tan oil. ESMSmm/z=614 [M+Na]⁺. This material was used without further purification.

Part B. To the product from Part A (0.24 g, 0.4 mmol) was added methanol(0.5 ml) and 4 N HCl in dioxane (4.0 ml). After stirring 2 hr, HPLCshowed no remaining starting material. Diethyl ether was added to form asolid but a gummy residue developed. The mixture was concentrated andthe oily residue was purified via reverse phase HPLC (C₁₈,acetonitrile/water/TFA) to afford 0.11 g (55%) of the desired product asa tan oil. ¹H NMR (N.O.E) confirmed the isomerized mixture as 70%trans:30% cis. HRMS calculated for C₂₅H₃₁NO₇S: 490.1899 [M+H]. found:490.1898.

Additional compounds can be prepared by one skilled in the art usingsimilar methods. Examples of such compounds include those having astructure corresponding to generic formula EX-J.

Example 29 Preparation of3,4-dihydro-N-[3-[4-[[tetrahydro-4-[(hydroxyamino)carbonyl]-2H-pyran-4-yl]sulfonyl]-phenoxypropyl]-2-(1H)-isoquinolinecarboxamide

Part A. To a solution of4-[[4-(3-aminopropoxy)-phenyl]sulfonyl]tetrahydro-2H-pyran-4-carboxylicacid 1,1-dimethylethyl ester, monohydrochloride (467 mg, 1.07 mmol,prepared in Example 1) in anhydrous chloroform (3 mL) at ambienttemperature was added triethylamine (170 uL, 1.22 mmol) and1,1′-carbonyldiimidazole (180 mg, 1.11 mmol). After 1 hr at 50° C.,1,2,3,4-tetrahydroisoquinoline (162 mg, 1.22 mmol) was added neat. Afteran additional 2 hr at 50° C. HPLC indicated complete reaction. Thereaction mixture was partitioned between ethyl acetate and 5% aqueouspotassium hydrogen sulfate. The organic layer was washed with saturatedsodium bicarbonate solution and brine, dried over sodium sulfate,filtered, and concentrated in vacuo to give a yellow oil. ESMS m/z=559[M+H]⁺. This material was used without further purification.

Part B. The product from Part A was taken up in neat trifluoroaceticacid (3 mL). After 13 hr. the trifluoroacetic acid was removed in vacuoat 50° C. to give the free acid. ESMS m/z=503 [M+H]⁺. To a solution ofthis material in anhydrous N,N-dimethylformamide (5 mL) was added1-hydroxybenzotriazole (176 mg, 1.30 mmol), triethylamine (500 uL, 3.59mmol), and tetrahydropyranhydroxylamine (254 mg, 2.17 mmol), followed by1-(3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (310 mg, 1.62mmol). The reaction mixture was heated at 40° C. for 4 hr, and thenstirred at ambient temperature overnight. The reaction mixture wasconcentrated in vacuo at 60° C. The residue was partitioned betweenethyl acetate and saturated sodium bicarbonate solution. The layers wereseparated, and the organic layer was washed with brine (3×), dried oversodium sulfate, filtered, and concentrated in vacuo. The crude productwas purified by flash chromatography to give 260 mg (40% from thestarting amine) of the desired THP protected hydroxamate as a whitesolid. ESMS m/z=624 [M+Na)⁺. HRMS calculated for C₃₀H₃₉N₃O₈S: 602.2536[M+H]⁺. found: 602.2546.

Part C. The product from Part B (252 mg, 0.42 mmol) was dissolved in 4NHCl in dioxane (5 mL) and methanol (500 uL). After 1 hr at ambienttemperature, the reaction mixture was poured into rapidly stirringdiethyl ether. A white solid was collected and dried over P205 undervacuum. The title compound was obtained as a white solid. ESMS m/z=518[M+H]⁺. HRMS calculated for C₂₅H₃₁N₃O₇S : 518.1961 [M+H]⁺. found:518.1961.

Additional compounds can be prepared by one skilled in the art usingsimilar methods (urea formation also can be achieved by coupling thestarting amine with and an isocyanate). Examples of such compoundsinclude those having a structure corresponding to generic formula EX-K.

Example 30 Preparation oftetrahydro-N-hydroxy-4-[[4-[3-[4-(4-methoxyphenyl)-2-oxazolyl]propoxyl]phenyl]sulfonyl]-2Hpyran-4-carboxamide

Part A. To a solution of4-[[4-(3-carboxypropoxy)phenyl]sulfonyl]tetrahydro-2H-pyran-4-carboxylicacid, 1,1-dimethylethyl ester (3.2 g, 7.5 mmol, prepared as in Example7) in acetone (15 mL) was added 2-bromo-4-methoxyacetophenone (1.72 g,7.5 mmol) and potassium carbonate (1.04 g, 7.5 mmol). The reactionmixture was stirred at ambient temperature for 3 hr. The reactionmixture was filtered, and the cake washed with acetone. The acetonesolution was concentrated in vacuo. Purification by flash columnchromatography using ethyl acetate/hexanes provided 3.68 g (85%) of thesubstituted ester as a white solid. ESMS m/z=599 [M+Na]⁺.

Part B. The product from Part A (3.6 g, 6.25 mmol) was refluxed inacetic acid (12 mL) with ammonium acetate (2.41 g, 31.25 mmol) for 24hr. The reaction was diluted with ethyl acetate (50 mL) and washed 2times with water (25 mL) and filtered. The ethyl acetate filtrate wasextracted with a 10% aqueous NaOH (50 mL). The basic solution was thenacidified to a pH of 1, and then extracted with ethyl acetate (25 mL).The organic solution was then washed with water (25 mL), dried oversodium sulfate, filtered, and concentrated in vacuo to give 1.5 g (48%)of the carboxylic acid of the oxazole as a brown solid. ESMS m/z=502[M+H]⁺.

Part C. In dry equipment under nitrogen, the carboxylic acid from Part B(1.3 g, 2.59 mmol) was dissolved in dry N,N-dimethylformamide (5 mL),and the remaining reagents were added to the solution in the followingorder: 1-hydroxybenzotriazole (490 mg, 3.63 mmol), triethylamine (0.43mL, 3.11 mmol), tetrahydropyranhydroxylamine (364 mg, 3.11 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (746 mg,3.89 mmol). After 12 hr at 40° C., the reaction was concentrated invacuo. The residue was taken up in ethyl acetate, washed with water,saturated sodium bicarbonate solution, and brine, dried over sodiumsulfate, filtered, and concentrated in vacuo. Purification by flashcolumn chromatography using ethyl acetate/hexanes provided 0.70 g (450)of the THP hydroxamate as a white foam. ESMS m/z=601 [M+H]⁺.

Part D. To a solution of the product from Part C (0.6 g, 1.0 mmol) in1,4-dioxane (1.0 mL) was added 4N HCl in dioxane (1.25 mL, 5 mmol) andmethanol (0.13 mL). After 1 hr at ambient temperature, the reaction wasdiluted with ethyl acetate and washed with water, dried over sodiumsulfate, filtered, and concentrated in vacuo. Methylene chloride (20 mL)was added, and the solution was stripped to afford 0.29 g (56%) of thetitle compound as a light pink solid. HRMS calculated for C₂₅H₂₈N₂O₈S:517.1645 [M+H]⁺. found: 517.1651.

Additional compounds can be prepared by one skilled in the art usingsimilar methods. Examples of such compounds include those having astructure corresponding to generic formula EX-L.

Example 31 Preparation oftetrahydro-N-hydroxy-4-[[4-[3-[3[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl]propoxy]phenyl]sulfonyl]-2H-pyran-4-carboxamide

Part A. In dry equipment under nitrogen,4-[[4-(3carboxypropoxy)phenyl]sulfonyl]tetrahydro-2H-pyran-4-carboxylicacid, 1,1-dimethylethyl ester (2.57 g, 6.0 mmol, prepared as in Example7) was dissolved in dry N,N-dimethylformamide (12 mL), and the remainingreagents were added to the solution in the following order:1-hydroxybenzotriazole hydrate (1.13 g, 8.4 mmol), triethylamine (1.0mL, 7.2 mmol), 4-(trifluoromethoxy)benzamidoxime (1.58 g, 7.2 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.73 g, 9.0mmol). After 2 hr at 35° C., the reaction was concentrated in vacuo. Theresidue was taken up in ethyl acetate, washed with water, saturatedsodium bicarbonate solution, and brine, dried over sodium sulfate,filtered, and concentrated in vacuo. Purification by flash columnchromatography using ethyl acetate/hexanes afforded 3.05 g (81%) of thedesired product as a clear glass. ESMS m/z=631 [M+Na]⁺.

Part B. The product from Part A (2.9 g, 4.60 mmol) was heated at 90° C.in toluene (15 mL) for 30 hr. The reaction was concentrated in vacuo.Purification by column chromatography using ethyl acetate/hexanesafforded 2.06 g (73%) of the oxadiazole as a white solid. ESMS m/z=635[M+Na]⁺.

Part C. The product from Part B (2.0 g, 3.27 mmol) was dissolved intrifluoroacetic acid (8 mL) and stirred at ambient temperature for 2 hr.The reaction was diluted with methylene chloride (10 mL) andconcentrated in vacuo. Methylene chloride (10 mL) was added to theresidue and concentrated in vacuo again to provide 1.8 g (99%) of thefree acid as an off—white solid. ESMS m/z=557 [M+H]⁺.

Part D. In dry equipment under nitrogen, the product from Part C (1.7 g,3.06 mmol) was dissolved in dry N,N-dimethylformamide (6 mL), and theremaining reagents were added to the solution in the following order:1-hydroxybenzotriazole hydrate (578 mg, 4.28 mmol), triethylamine (0.51mL, 3.67 mmol), tetrahydropyranhydroxylamine (429 mg, 3.67 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (879 mg,4.59 mmol). After 90 min at 40° C., the reaction was concentrated invacuo. The residue was taken up in ethyl acetate, washed with water,saturated sodium bicarbonate solution, and brine, dried over sodiumsulfate, filtered, and concentrated in vacuo. Purification by flashcolumn chromatography using ethyl acetate/hexanes provided 1.9 g (95%)of the THP hydroxamate as a white foam. ESMS m/z=678 [M+Na]⁺.

Part E. To a solution of the product from Part D (1.8 g, 2.75 mmol) in1,4-dioxane (1.0 mL) was added 4N HCl in dioxane (3.5 mL, 13.7 mmol) andmethanol (0.35 mL). After 2 hr at ambient temperature, the reaction wasdiluted with ethyl acetate and washed with water, dried over sodiumsulfate, filtered, and concentrated in vacuo. Reverse phasechromatography provided 1.12 g (71%) of the title compound as a whitesolid. HRMS calculated for C₂₄H₂₄N₃O₈S₁F₃: 572.1314 [M+H]⁺. found:572.1290.

Example 32 Preparation oftetrahydro-N-hydroxy-4-[[4-[3-[5-(2-methylphenyl)-1,3,4oxadiazol-2-yl]propoxy]phenyl]sulfonyl]-2H-pyran-4-carboxamide

Part A. In dry equipment under nitrogen,4-[[4-(3-carboxypropoxy)phenyl]sulfonyl]tetrahydro-2H-pyran-4-carboxylicacid, 1,1-dimethylethyl ester (2.14 g, 5.0 mmol, prepared as in Example7) was dissolved in dry N,N-dimethylformamide (10 mL), and the remainingreagents were added to the solution in the following order:1-hydroxybenzotriazole hydrate (945 mg, 7.0 mmol), triethylamine (0.84mL, 6.0 mmol), o-toluic hydrazide (901 mg, 6.0 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.44 g, 7.5mmol). After 2 hr at 35° C., the reaction was concentrated in vacuo. Theresidue was taken up in ethyl acetate; washed with water, saturatedsodium bicarbonate solution, and brine; dried over sodium sulfate;filtered; and concentrated in vacuo. Purification by flash columnchromatography using ethyl acetate/hexanes provided 2.32 g (83%) of thedesired product as a white foam. ESMS m/z=583 [M+Na]⁺.

Part B. The product from Part A (2.1 g, 3.75 mmol) was heated to refluxin toluene (25 mL) with toluenesulfonic acid (100 mg) for 4 hr. Thereaction was concentrated in vacuo. Recrystalization from hot methanolprovided 1.6 g (88%) of the free acid of the oxadiazole as a whitesolid. ESMS m/z=487 [M+Na]⁺.

Part C. In dry equipment under nitrogen, the product from Part B (1.5 g,3.09 mmol) was dissolved in dry N,N-dimethylformamide (6 mL), and theremaining reagents were added to the solution in the following order:1-hydroxybenzotriazole hydrate (578 mg, 4.28 mmol), triethylamine (0.51mL, 3.67 mmol), tetrahydropyranhydroxylamine (429 mg, 3.67 mmol), and1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (879 mg,4.59 mmol). After 6 hr at 40° C., the reaction was concentrated invacuo. The residue was taken up in ethyl acetate; washed with water,saturated sodium bicarbonate solution, and brine; dried over sodiumsulfate; filtered; and concentrated in vacuo. Purification by flashcolumn chromatography using ethyl acetate/hexanes provided 1.53 g (85%)of the THP hydroxamate as a white foam. ESMS m/z=608 [M+Na]⁺.

Part D. To a solution of the product from Part C (1.4 g, 2.39 mmol) in1,4dioxane (1.0 mL) was added 4N HCl in dioxane (6 mL, 23.9 mmol) andmethanol (0.6 mL). After 2 hr at ambient temperature, the reaction wasdiluted with ethyl acetate and washed with water, dried over sodiumsulfate, filtered, and concentrated in vacuo. Reverse phasechromatography provided 1.02 g (85%) of the title compound as a whitesolid. HRMS calculated for C₂₄H₂₇N₃O₇S]: 502.1648 [M+H]⁺. found:502.1652.

Additional compounds can be prepared by one skilled in the art usingsimilar methods. Examples of such compounds include those having astructure corresponding to generic formula EX-M.

Example 33 Preparation of4-[[4-[3-(2-benzoxazolylthio)propoxy]phenyl]sulfonyl]tetrahydro-N-N-hydroxy-2H-pyran-4-carboxamide

Part A. To a solution of 2-mercaptobenzoxazole (290 mg, 1.92 mmol) inN,N-dimethylformamide (5 mL) at 0° C. was added NaH (128 mg, 1.92 mmol,60% dispersion in mineral oil). After 30 min,tetrahydro-4-[[4-[3-[(methylsulfonyl)oxy]propoxy]phenyl]sulfonyl]-N-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-pyran-4-carboxamide(1.0 g, 1.92 mmol, prepared as in Example 29) was added, and thesolution was stirred for 2 hr at 65° C. The solution was partitionedbetween ethyl acetate and water. The organic layer was washed with waterand brine, dried over sodium sulfate, filtered, and concentrated invacuo to afford 510 mg (46%) of the thiobenzoxazole as a crude dark oil.ESMS m/z=577 [M+H]⁺.

Part B. To a solution of the crude thiobenzoxazole of Part A (505 mg,0.88 mmol) in 1,4-dioxane (5 mL) was added 4 N HCl in dioxane (5 mL),and was stirred for 2 hr. Purification by reverse phase BPLC (C₁₈,acetonitrile/water) provided 257 mg (60%) of the title compound as awhite solid. ESMS m/z=493 [M+H]⁺. HRMS calculated for C₂₂H₂₄N₂O₇S₂:493.1103, found 493.1122. Analytical calculation forC₂₂H₂₄N₂O₇S₂.0.3H₂O: C, 53.06; H, 4.98; N, 5.63; S, 12.88. Found: C,53.03; N, 5.62; S 12.69.

Additional compounds can be prepared by one skilled in the art usingsimilar methods. Examples of such compounds include those having astructure corresponding to generic formula EX-N.

Example 34 Preparation of4-[[4-[[tetrehydro-4-[(hydroxyamino)carbonyl]-2H-pyran-4yl]sulfonyl]cyclohexyl]oxy]butylester 3,4-dihydro-2(1H)-isoquinolinecarboxylic acid

Part A. To a solution oftetrahydro-4-[[4-[4-[(methyl-sulfonyl)oxy]butoxy]phenyl]sulfonyl]-N-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-pyran-4-carboxamide(200 mg, 0.37 mmol, synthesized in a fashion similar to Example 29) inanhydrous N,N-dimethylformamide (2 mL) was added to1,2,3,4-tetrahydroisoquinoline (0.24 mL, 1.9 mmol) and cesium carbonate(0.62 g, 1.9 mmol). The reaction mixture was stirred at ambienttemperature overnight. The crude reaction mix was poured onto a 20 mLChemElut tube (celite) prewetted with 15 mL of water, and eluted with1:1 ethyl acetate:methylene chloride. Purification by reverse phase HPLC(C18, acetonitrile/water), followed by treatment with 2 mL of 4N HCl indioxane, provided 12.2 mg (6.2%) of the desired product as an amorphoussolid after lyophilization. ESMS m/z=531 [M+H])′. HRMS calculated forC₂₆H₃₃N₂O₈S: 533.1958 [M+H]⁺. found: 533.1943.

Additional compounds can be prepared by one skilled in the art usingsimilar methods. Examples of such compounds include those having astructure corresponding to generic formula EX-O.

Example 35 Preparation of4-[[4-[4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butyl]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A. A solution of 4-bromobenzenethiol (28.5 g, 151 mmol) inN,N-dimethylformamide (250 mL) was purged with nitrogen for 10 min andthen potassium carbonate (22.9 g, 166 mmol) was added. After purging foranother 10 min with nitrogen, t-butyl bromoacetate (24.5 g, 166 mmol)was added, and the reaction was stirred at ambient temperature for 1 hr.The reaction was chilled to 0° C. and diluted with water (250 mL). Theslurry was extracted with ethyl acetate. The organic layer was washedwith water, saturated sodium bicarbonate solution, and brine; dried oversodium sulfate; filtered; and concentrated in vacuo to provide 49.8 g(100%) of the sulfide as a light yellow oil. ESMS m/z=3 2 0 [M+NH4]⁺.

Part B. To a solution of the product from Part A (45.67 g, 151 mmol) intetrahydrofuran (300 mL) was added water (75 mL) and Oxone™ (278.5 g,453 mmol) at 20° C. An exotherm to 43° C. was observed. After 3 hr, thereaction was filtered, and the cake was washed well withtetrahydrofuran. The filtrate was concentrated in vacuo to 1 third thevolume. The residue was taken up in ethyl acetate, washed with brine,dried over magnesium sulfate, filtered, and concentrated in vacuo togive 51.0 g (100%) of the sulfone as a crystalline solid. ESMS m/z=335[M+H]⁺.

Part C. To a solution of the product from Part B (23.45 g, 16 mmol) inN,N-dimethylformamide (140 mL) was added potassium carbonate (19.3 g,140 mmol), bis-(2-bromoethylether (9.1 mL, 70 mmol), and 18-Crown-6 (1g). The slurry was stirred at 60° C. After 16 hr, the reaction wasfiltered, and the filtrate was concentrated in vacuo. The residue wastaken up in ethyl acetate, washed with water (3×) and brine, dried oversodium sulfate, filtered, and concentrated in vacuo. The product wasrecrystallized from methanol to provide 19.79 g (70%) of the desiredcompound as a white solid. (ESMS m/z=405 [M+H]⁺.

Part D. To a solution of N-(3-buten-1-yl)phthalimide (1.2 g, 5.97 mmol)in anhydrous tetrahydrofuran (3 mL) at 0° C. was added 0.5 M9-borobicyclononane in tetrahydrofuran (11.9 mL, 5.97 mmol) dropwise.The resultant solution was stirred with cooling for 10 min, and then theice bath was removed. After 18 hr, the product from Part C (1 g, 2.98mmol), tetrakis(triphenyl-phosphine)palladium(0) (172 mg, 0.15 mmol) and2 M sodium carbonate (3 mL, 6 mmol) were added, and the reaction mixturewas heated to 65° C. for 2 hr. After cooling to ambient temperature, thesolution was concentrated in vacuo. The residue was partitioned betweenethyl acetate (50 mL) and water (50 mL). The layers were separated, andthe organic layer was washed with water (50 mL) and brine (50 mL), driedover magnesium sulfate, filtered, and concentrated in vacuo.Purification by flash column chromatography using 25-50% ethylacetate/hexanes yielded 1.21 g of the desired compound as an off-whitesolid. HRMS calculated for C₂₈H₃₇N₂O₇S: 545.2321 [M+H]⁺. found:545.2311.

Part E. To a solution of the product from Part D (1.16 g, 2.2 mmol) in,anhydrous methylene chloride (20 mL) at ambient temperature was addedtrifluoroacetic acid (20 mL). The solution was stirred for 2 hr, andthen concentrated in vacuo. The resulting residue was dissolved inmethanol (50 mL) and concentrated in vacuo, and subsequently dissolvedin methylene chloride (50 mL) and concentrated in vacuo. Triturationwith hexanes yielded 0.98 g of the carboxylic acid as an off-whitesolid. HRMS calculated for C₂₈H₃₇N₂O₇S: 489.1695 [M+NH₄]. found:489.1702.

Part F. To a solution of the product from Part E (0.95 g, 2.01 mmol) ina mixture of methylene chloride (4 mL) and N,N-dimethylformamide (4 mL)was added triethylamine (0.28 mL, 2.01 mmol), 1-hydroxybenzotriazole(0.407 g, 3.015 mmol), and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.538 g,2.814 mmol). After 10 min, additional triethylamine (0.56 mL, 4.02 mmol)and tetrahydropyranhydroxylamine (0.706 g, 6.03 mmol) were added. Thesolution was warmed to 38° C. and stirred for 20 hr. The mixture waspartitioned between ethyl acetate (50 mL) and water (50 mL). The organiclayer was washed with 1 M HCl (50 mL), water, brine. After drying overmagnesium sulfate, the organic layer was concentrated to give 1.31 g ofan off white solid. Purification by flash column chromatography using25-50% ethyl acetate/hexanes yielded 1.05 g of the pure product as awhite solid. HRMS calculated for C₂₉H₃₄N₂O₈SNa: 593.1934 [M+Na]. found:593.1967.

Part G. To a solution of the product from Part F above (0.255 g, 0.446mmol) in a mixture of methanol (3 mL) and dioxane (3 mL) was added 4 NHCl in dioxane (3 mL). The mixture was stirred at ambient temperaturefor 10 min, and then concentrated in vacuo. Trituration with diethylether/hexanes yielded 224 mg of the title compound as a white solid.HRMS calculated for C₂₄H₂₇N₂O₇S: 487.1539 [M+H]. found: 487.1559.

Example 36 Preparation of 2H-pyran-4-carboxamide,tetrahydro-N-hydroxy-4[[4-[3-(2-naphthalenyl)propoxy]-phenyl]sulfonyl]

To a solution of(tetrahydro-4-[[4-(2propenyloxy)phenyl]sulfonyl]-N-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-pyran-4-carboxamide(200 mg, 0.47 mmol, prepared as in Example 35) in tetrahydrofuran (1 mL)was added 0.5 M 9-borobicyclononane (0.94 mL, 0.47 mmol). The solutionwas stirred at ambient temperature for 16 hr. To this solution was added2 M sodium carbonate (0.5 mL, 1 mmol), 2-bromonaphthalenylene (108 mg,0.52 mmol), and tetrakis(triphenylphosphine)palladium(0) (54 mg, 0.047mmol). The mixture was heated to 65° C. for 4 hr, and then cooled toambient temperature. Saturated ammonium chloride solution (3 mL) wasadded to the reaction mixture. The resulting mixture was filteredthrough a small column of celite. The column was washed with ethylacetate (35 mL). The eluant was concentrated in vacuo, and the residuewas dissolved in methanol (3 mL), dioxane (3 mL), and 4 N HCl indioxane. After 10 min, the solution was concentrated in vacuo, and theresidue purified by preparative reverse phase HPLC (10-90%acetonitrile/0.05% TFA in water) yielding 20 mg of the title compound asa white solid. HRMS calculated for C₂₅H₂₈NO₆S: 470.1670 [M+H]. found:470.1614.

Additional compounds can be prepared by one skilled in the art usingsimilar methods. Examples of such compounds include those having astructure corresponding to generic formula EX-P.

Example 37 Preparation of4-[[4-[-3-(2-benzoxazolyl)propoxy]phenyl]sulfonyl]tetrahydro-N-hydroxy-2H-pyran-4-carboxamide

Part A. To a solution of4-[[4-(3-carboxypropoxy)phenyl]sulfonyl]tetrahydro-2H-pyran-4-carboxylicacid, 1,1-dimethylethyl ester (3.0 g, 7.0 mmol) in N,N-dimethylformamide(14 mL) was added 1-(3-dimethylamino-propyl)-3-ethylcarbodiimidehydrochloride (1.88 g, 9.8 mmol) and 1-hydroxybenzotriazole (1.32 g, 9.8mmol). The resulting suspension became a clear amber solution afterstirring at 50° C. for 1.5 hr. The reaction was then treated with2-aminophenol (0.76 g, 7.0 mmol), followed by N-methylmorpholine (2.3mL, 21.0 mmol). The reaction was stirred at 50° C. overnight. After 21hr, the reaction was partitioned between ethyl acetate (50 mL) and water(50 mL). The aqueous layer was extracted with ethyl acetate. The organiclayers were combined and washed with saturated sodium bicarbonatesolution, water, 1:1 solution of water:brine, and brine; dried oversodium sulfate; filtered; and concentrated in vacuo. The resulting oilwas purified on silica gel using ethyl acetate/hexanes to afford 2.98 g(82%) of the amide as an amber oil. ESMS m/z=542 [M+Na]⁺.

Part B. To a suspension of the product from Part A the (1.59 g, 3.1mmol) toluene (50.0 mL) was added p-toluenesulfonic acid (0.12 g, 0.6mmol), and the resulting mixture heated at reflux under Dean-Starkconditions. After 39 hr, the reaction was concentrated in vacuo, and theresulting residue was partitioned between ethyl acetate and 1 M aqueoushydrochloric acid. The organic layer was washed with 1 M aqueoushydrochloric acid, water, and brine; dried over sodium sulfate;filtered; and concentrated in vacuo to afford 1.25 g (92%) of the crudecarboxylic acid benzoxazole as a tan, white solid. ESMS m/z=446 [M+H]⁺.

Part C. To a solution of the product from Part B (0.98 g, 2.2 mmol) inN,N-dimethylformamide (10.0 mL) was added1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (0.59 g,3.1 mmol) and 1-hydroxybenzotriazole (0.42 g, 3.1 mmol). The resultingsuspension became a clear amber solution after stirring at 50° C. for0.5 hr. The reaction was then treated with tetrahydropyranhydroxylamine(0.36 g, 3.1 mmol), followed by N-methylmorpholine (0.73 mL, 6.6 mmol).The reaction was stirred at 50° C. overnight. After 12 hr, the reactionwas partitioned between ethyl acetate and water. The aqueous layer wasextracted with ethyl acetate. The organic layers were combined andwashed with saturated sodium bicarbonate solution, water, 1:1 solutionof water:brine, and brine; dried over sodium sulfate; filtered; andconcentrated in vacuo. The resulting oil was purified on silica gelusing ethyl acetate/hexanes as eluant to afford 1.2 g (98%) of the THPhydroxamate benzoxazole as an amber oil. ESMS m/z=545 [M+H]⁺.

Part D. To a solution of the product from Part C (0.104 g, 0.19 mmol) ina mixture of methanol (0.3 mL) and dioxane (2 mL) was added 4 N HCl indioxane (0.5 mL). The mixture was stirred at ambient temperature for 30min, concentrated in half in vacuo, and diluted with diethyl ether.Filtration afforded 17 mg (20%) of the title compound as a tan solid.HRMS calculated for C₂₂H₂₄N₂O₇S: 461.1382 [M+H]. found: 461.1374.

Additional compounds can be prepared by one skilled in the art usingsimilar methods. Examples of such compounds include those having astructure corresponding to generic formula EX-Q.

Example 38 Preparation of

Part A. Preparation of:

To a solution of ethyl4-[(4-fluorophenyl)sulfonyl]piperidine-4-carboxylate hydrochloride (60.0g, 170 mmol) in methanol (600 mL), were added acetic acid (97 mL, 1.7mole), [(1-ethoxycyclopropyl)oxy]trimethylsilane (102 mL, 510 mmol) and4A molecular sieves (55 g) followed by sodium cyanoborohydride (28.8 g,459 mmol). The solution was stirred at ambient temperature overnight,then refluxed for 6 hr. The reaction mixture was filtered through celiteand concentrated to solid/oil mix. Ethyl acetate and saturated sodiumbicarbonate were added very carefully. When aqueous layer stayed basic,the layers were separated and the organic layer was washed 3 times withsaturated sodium bicarbonate, then with brine and then dried over sodiumsulfate. Concentration in vacuo and crystallization from ethylacetate/hexane provided the n-cyclopropyl compound as an off white solid(53.8 g, 88.8%). ESMS, 356 (M+H).

Part B. Preparation of:

To a solution of 3-(3-bromophenyl)propionic acid (10.0 g, 43.7 mmol) inanhydrous THF (150 mL) was added 1.0 M BH₃.THF (150 mL, 150 mmol) viaaddition funnel. After BH₃.THF was added, the reaction was refluxed for18 hrs. The reaction was quenched with water (100 mL) and 1N HCl (300mL). The solution was saturated with sodium chloride and extracted withethyl acetate. The organic extract was washed with brine and dried overmagnesium sulfate. The organic material was purified by chromatographyon silica gel eluting with ethyl acetate in hexane to produce 9.39 g(100%) of the desired alcohol as a colorless oil. NMR (CDCl₃) 671.82-1.89 (m, 2H), 2.67 (t, 2H), 3.64 (t, 2H), 7.11 7.15 (m, 1H),7.29-7.31 (m, 1H), 7.34 (s, 1H).

Part C. Preparation of:

In a flask were combined the alcohol from Part B (3.43 g, 16.0 mmol),phenyl boronic acid (2.93 g, 24.0 mmol), palladiumtetrakistriphenylphosphine (0.92 g, 0.8 mmol), 2M cesium carbonate (24mL, 48 mmol) and dimethoxyethylether (48 mL). The mixture was stirredvigorously under nitrogen at reflux. After 1.5 hr the reaction wascooled to ambient temperature, diluted with water and extracted withether 3 times. The combined organic extracts were washed with brine anddried over magnesium sulfate. 2.74 g (81% yield) purified product wasobtained as a crystalline solid by chromatography (on silica, ethylacetate/hexane). NMR (CDCl₃) δ 1.91-1.98 (m, 2H), 2.77 (t, 2H), 3.71 (t,2H), 7.19 (d, 1H), 7.31-7.38 (m, 2H), 7.41-7.45 (m, 4H), 7.58 (d, 2H).

Part D. Preparation of:

To a solution of the alcohol from Part C (2.7 g, 12.7 mmol) in anhydrousdimethylformamide (12 mL) at 0° C. was added 60% sodium hydride (0.58 g,14.5 mmol) in portions. After that the reaction was stirred at 0° C. for15 min and then at ambient temperature for 15 min. The reaction mixturewas cooled to 0° C. and the cyclopropyl compound from Part A (4.3 g,12.4 mmol) in anhydrous dimethylformamide (10 mL) was added slowly. Uponcompletion of addition, ice bath was removed and the reaction stirred atambient temperature for 1 hr the reaction, then diluted with water andextracted with ethyl acetate 3 times. The combined organic extracts werewashed with saturated NaHC0₃ and brine and dried over sodium sulfate.After concentration 4.63 g of material was obtained. This material wasused without purification.

Part E. Preparation of:

The ester of Part D (4.61 g, 8.4 mmol) was hydrolyzed in 1:1:0.56mixture of ethanol:1,4-dioxane:6N NaOH (25.6 mL) at 60° C. The solutionwas concentrated in vacuo, diluted with water and extracted with etherto remove color. Acidification with 1N HCl caused precipitation of theacid which was collected by filtration, washed with water and hexane anddried under high vacuum yielding the acid as an off white solid (3.45 g,79% yield). ESMS_(m/z)=520 (M+H)⁺. This material was used withoutpurification.

Part F. Preparation of:

To a suspension of the crude acid of Part E (3.44 g, 6.62 mmol) in DMF(27 mL) were added HOBt (1.52 g, 9.93 mmol), N-methylmorpholine (2.2 mL,19.9 mmol) and EDC (1.77 g, 9.27 mmol). After heating at 40° C., acidslowly went into solution. When reaction was clear, it was cooled toambient temperature and THP-hydroxylamine (1.16 g, 9.93 mmol) was added.The solution was stirred for 18 hr at ambient temperature. The solutionwas partitioned between ethyl acetate and water. The organic layer waswashed with water and brine and dried over magnesium sulfate.Chromatography (on silica, ethyl acetate/hexanes) provided the protectedhydroxamate as a crystalline solid (3.20 g, 74%). NMR δ 0.36 (d, 4H),1.50-1.92 (m, 8H), 2.05-2.21 (m, 3H), 2.32 (s, 2H), 2.86 (t, 2H), 2.98(s, 2H), 3.69 (d, 1H), 3.96-4.07 (m, 3H), 5.00 (s, 1H), 6.95 (d, 2H),7.17 (d, 1H), 7.30-7.43 (m, 6H), 7.54 (d, 2H), 7.73 (d, 2H), 9.41 (s,1H).

Part G. Preparation of:

To the semi pure product from Part F (3.03 g, 4.89 mmol) in methanol (10mL) and 1,4-dioxane (10 mL) was added 4M hydrochloric acid in1,4-dioxane (10 mL) and after stirring 20-30 min the product began tocrystallize out. Reverse phase chromatography (on C₁₈,acetonitrile/water) to remove color followed by conversion to HCl saltwith methanol and 4N HCl/dioxane then recrystallization frommethanol/iso propanol provided 1.95 g (70%) of the title compound as ahydrochloric acid salt that was colorless. ESMS_(m/z)=535 (M+H)⁺. HRMScalcd. for C₃₀H₃₅N₂₀O₅S H: 535.2261 (M+H)⁺. Found: 535.2270.

Example 39 Preparation of

Part A. Preparation of:

A solution of the alcohol from Part B, Example 38 (4.4 g, 20.4 mmol),tert-butyl 4[(4-fluorophenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylate(5.0 g, 14.6 mmol) and Cs₂CO₃ (9.5 g, 29.2 mmol) in anhydrousdimethylformamide (30 mL) was stirred at 80° C. for 30 hr. The reactionwas diluted with water (300 mL) and extracted with ethyl acetate (3times). The combined organic extracts were washed with brine and driedover magnesium sulfate. Crystallization from methylene chloride/hexanegave 6.95 g (88%) of the product as a colorless solid. ESMS_(m/z)=556(M+NH₄)⁺. HRMS calcd. for C₂₅H₃₅BrNO₆S H: 556.1368 (M+NH₄)⁺. Found:556.1318.

Part B. Preparation of:

The ester of Part A (6.81 g, 12.6 mmol) was hydrolyzed in 1:1TFA:methylene chloride (50 mL) at ambient temperature for 1.5 hr. Thesolution was concentrated in vacuo, taken up in toluene, concentrated toa colorless solid and dried under high vacuum yielding the acid as animpure white solid (6.28 g, 100% yield). ESMS_(m/z)=500 (M+NH₄)⁺. HRMScalcd. for C₂₁H₂₃BrO₆SNH₄: 500.0742 (M+NH₄)⁺. Found: 500.0761.

Part C. Preparation of:

To a suspension of the impure acid of Part B (theoretically 12.5 mmol)in anhydrous DMF (25 mL) were added HOBt (2.0 g, 15 mmol), triethylamine(5.2 mL, 37.5 mmol) and EDC (3.4 g, 17.5 mmol). After heating at 40° C.for 1 hr, THP hydroxylamine (4.4 g, 37.5 mmol) was added. The solutionwas stirred for 18 hr at ambient temperature, then at 40° C. for 3 hr.The reaction was diluted with water (150 mL) and extracted with ethylacetate (3 times). The combined organic extracts were washed with brineand dried over magnesium sulfate. Chromatography (on silica, ethylacetate/hexanes) provided the protected hydroxamate as a viscous oil(4.32 g, 60%). ESMS_(m/z)=601 (M+NH₄)⁺. HRMS calcd. for C₂₆H₃₂BrNO₇SNH₄:601.1410 (M+NH₄)⁺. Found: 601.1448.

Part D. Preparation of:

In a vial were combined the aryl bromide from Part C (0.20 g, 0.34 mmol)in 1 mL of dimethoxyethyl ether, 4-fluorobenzeneboronic acid (74 mg,0.53 mmol), palladium tetrakistriphenylphosphine (23 mg, 0.02 mmol) in0.5 mL of dimethoxyethyl ether and 2M cesium carbonate (0.51 mL, 1.02mmol). The mixture stirred vigorously at 65° C. for 18 hr. The eactionmixture was poured onto 5 mL Chem-Elut tube pre-wetted with 3 mL ofwater and eluted with 10% ethyl acetate/methylene chloride.Concentration under nitrogen gave 254 mg of crude product that wascarried on as is.

Part E. Preparation of:

The crude product from Part D (254 mg) was taken up in 4M hydrochloricacid in 1,4-dioxane (2 mL) and methanol (1-2 mL) and stirred for 2 hrthen concentrated. Material purified by reverse phase chromatography (onC₁₈, acetonitrile/water). Product crystallized upon concentrationyielding 108.5 mg (62%) of the title compound as colorless solid.ESMS_(m/z)=514 (M+H)⁺. HRMS calcd. for C₂₇H₂₉FNOS: 514.1700 (M+H)⁺.Found: 514.1694.

Example 40 Preparation of

Part A. Preparation of:

3-bromophenethyl alcohol (5.0 g, 24.9 mmol) and2-(tributylstannyl)pyridine (13.6 g, 37.4 mmol) were combined in a roundbottom flask with PdCl₂(PPh₃)₂ (0.84 g, 1.2 mmol), CuI (0.23 g, 1.2mmol) and anhydrous THF (100 mL) and heated to reflux. After refluxingovernight, additional PdCl₂(PPh₃)₂ (0.84 g, 1.2 mmol) and CuI (0.23 g,1.2 mmol) were added and the reaction refluxed overnight. The reactionwas cooled to ambient temperature, Norit A charcoal added, the mixturestirred and then filtered through a bed of celite. Chromatography (onsilica, ethyl acetate/hexanes) provided the alcohol as an orange oil(2.76 g, 55.8%). ESMS_(m/z)=200 (M+H)⁺.

Part B. Preparation of:

To a solution of the alcohol from Part A (2.75 g, 13.8 mmol) inanhydrous dimethylformamide (13 mL) at 0° C. was added 60% sodiumhydride (0.58 g, 14.4 mmol) in portions. After completion of theaddition, the reaction was stirred at 0° C. for 30 min. tert-butyl4-[(4-fluorophenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylate (4.51 g,13.1 mmol) in anhydrous dimethylformamide (10 mL) was added over 15 min.Upon completion of addition, the ice bath was removed and the reactionstirred at ambient temperature. After 1.5 hr the reaction was dilutedwith water and extracted with ethyl acetate 3 times. The combinedorganics were washed with saturated NaCl and dried over magnesiumsulfate. Chromatography (on silica, ethyl acetate/hexanes) provided theproduct as an off white solid (5.44 g, 79%). ESMS_(m/z)=524 (M+H)⁺.

Part C. Preparation of:

The ester of Part B (5.45 g, 10.4 mmol) was hydrolyzed in 1:1 mixture ofTFA:methylene chloride (30 mL) at ambient temperature for 8 hr. Thesolution was concentrated in vacuo, taken up in methanol and 4N HCl indioxane and concentrated. This was repeated to give a viscous oil (6.25g, >100% yield). This material was used without further purification.

Part D. Preparation of:

To a suspension of the crude acid of Part C (assume 10.4 mmol) in NMP(40 mL) were added HOBt (2.39 g, 15.6 mmol), N-methylmorpholine (3.4 mL,31.2 mmol) and EDC (2.79 g, 14.6 mmol). After heating at 40° C.overnight, HPLC still showed acid to be present so additional added HOBt(2.39 g, 15.6 mmol), N-methylmorpholine (3.4 mL, 31.2 mmol) and EDC(2.79 g, 14.6 mmol) were added. After 1 hr at 40° C., THP hydroxylamine(3.66 g, 31.2 mmol) was added. After 1 hr, the solution was diluted withwater and extracted with ethyl acetate 3 times. The combined organiclayers were washed with brine and dried over magnesium sulfate.Chromatography (on silica, ethyl acetate/hexanes) provided the protectedhydroxamate as a colorless foam (5.05 g, 85.7). ESMS_(m/z)=567 (M+H)⁺.

Part E. Preparation of:

To the product from Part D (5.05 g, 8.91 mmol) in methanol (15 mL) and1,4-dioxane (15 mL) was added 4M hydrochloric acid in 1,4-dioxane (15mL) and after stirring 1 hr reaction was complete. Concentrationfollowed by crystallization from methanol/iso-propanol provided 3.88 g(84%) of the title compound as a hydrochloric acid salt that wascolorless. ESMS_(m/z)=483 (M+H)⁺. HRMS calcd. for C₂₅H₂₇N₂O₆S H:483.1584 (M+H)⁺. Found: 483.1585.

Example 41 Preparation of 1-ethyl-N-hydroxy4-{[4-(3-{3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5yl}propoxy)phenyl]sulfonyl}piperidine-4-carboxamidehydrochloride.

Part A. To a slurry of ethyl4[(4-fluorophenyl)sulfonyl]-4-piperidinecarboxylate, monohydrochloride(14.06 g, 40 mmol) in dimethylacetamide (80 mL) were added potassiumcarbonate (13.82 g, 100 mmol) and iodoethane (3.36 mL, 42 mmol). Theslurry was stirred at ambient temperature. After 3 hr the reaction wasconcentrated in vacuo. The residue was taken up in ethyl acetate, washedwith water three times, saturated sodium chloride solution, dried overNa₂SO₄, filtered, and concentrated in vacuo. Chromatography (on silica,methylene chloride/hexanes) provided the N-ethyl piperidine as a whitesolid (13.05 g, 95%).

Part B. In dry equipment under nitrogen, potassium trimethylsilonate(10.52 g, 73.8 mmol) was dissolved in dimethylsulfoxide (40 mL) andgamma-butyrolactone (4.26 mL, 55.4 mmol) was added over 5 min while thereaction temperature rose to 49 C. After stirring at ambient temperaturefor 90 min, sodium hydride (2.2 g of a 60% oil dispersion, 55.4 mmol)was added portion wise over 20 min and the reaction temperature rose to38° C. Gas evolution was also observed. After stirring at ambienttemperature for 40 min, a solution of the N-ethyl piperidine from Part A(12.66 g, 36.9 mmol) in dimethylsulfoxide (10 mL) was added over 10 minas the reaction rose to 8° C. The reaction was stirred at ambienttemperature for t30 min. The slurry was slowly poured into ice water(400 mL) and then extracted with hexanes (100 mL) two times followed bya diethyl ether extraction (100 mL). The aqueous layer was chilled to 5°C. and the pH adjusted to 7 with concentrated hydrochloric acid. Theaqueous solution was extracted with methylene chloride (150 mL) untilthere was no UV activity in the extract. The combined methylene chlorideextracts were washed with saturated sodium chloride solution, dried overNa₂SO₄, filtered, and concentrated in vacuo. The solid wasrecrystallized from isopropanol (65 mL) to give the butyric acid as awhite solid (8.2 g, 52%). LCMS_(m/z)=428 [M+H]⁺.

Part C. In dry equipment under nitrogen, the butyric acid from Part B(5.12 g, 12.0 mmol) was dissolved in dry dimethylacetamide (20 mL) andthe remaining reagents were added to the solution in the followingorder: N-hydroxybenzotriazole hydrate (2.43 g, 18.0 mmol), triethylamine(3.34 mL, 24.0 mmol), 4-(trifluoromethoxy)benzamidoxime (3.96 g, 18.0mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(4.6 g, 24.0 mmol). After 24 hr at 70° C., the reaction was concentratedin vacuo. The residue was taken up in ethyl acetate, washed with water,saturated NaHCO₃, saturated sodium chloride solution, dried over Na₂SO₄,filtered, and concentrated in vacuo. Chromatography (on silica, ethylacetate/methanol/hexanes) provided the oxadiazole as a light yellowsolid (5.05 g, 69%). LCMS_(m/z)=612 [M+H]⁺.

Part D. A slurry of the oxadiazole from Part C (4.9 g, 8.02 mmol), 2.5Nsodium hydroxide (9.6 mL, 24.06 mmol) and sodium hydroxide (1.28 g,32.08 mmol) in isopropanol (40 ml ) were stirred at 70° C. for 7 hr. Theheat was removed and the reaction diluted with water (100 ml) andchilled to 5° C. The pH was adjusted to 7 with concentrated hydrochloricacid. The solids were filtered, washed with hexanes, and dried in vacuoto give the carboxylic acid as a white solid (4.54 g, 97%).LCMS_(m/z)=584 [M+H]⁺.

Part E. In dry equipment under nitrogen, the carboxylic acid from Part D(4.5 g, 7.72 mmol) was dissolved in dry dimethylacetamide (15 ml ) andthe remaining reagents were added to the solution in the followingorder: N-hydroxybenzotriazole hydrate (1.56 g, 11.6 mmol), triethylamine(3.22 mL, 23.2 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1.35 g,11.6 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (2.96 g, 15.4 mmol). After 29 hr at 50° C., the reactionwas concentrated in vacuo. The residue was taken up in ethyl acetate,washed with water, saturated NaHtCO₃, saturated sodium chloridesolution, dried over Na₂SO₄, filtered, and concentrated in vacuo.Chromatography (on silica, ethyl acetate/methanol/hexanes) provided theTHP hydroxamate as a light yellow solid (2.4 g, 46%). LCMS_(m/z)=683[M+H]⁺.

Part F. To the THP hydroxamate from Part E (2.3 g, 3.37 mmol) was added4N HCl dioxane solution (8.4 mL, 33.7 mmol) and methanol (0.84 mL). Theslurry became very thick. Diethyl ether (50 ml ) was added to and after1 hr at ambient temperature the reaction was filtered under nitrogen.The solids were washed with diethyl ether (150 ml ) under nitrogen anddried in vacuo over phoshorus pentoxide to give the title compound as awhite solid (1.92 g, 91%). HRMS (ES+) M+H⁺ calculated forC₂₆H₂₉N₄O₇S₁F₃: 599.1787, found 599.1766.

Example 42 Preparation of

Part A. In dry equipment under nitrogen, potassium trimethylsilonate(42.76 g, 0.3 mol) was dissolved in dimethylsulfoxide (170 mL) andgamma-butyrolactone (17.31 mL, 0.225 mol) was added over 5 min while thereaction temperature rose to 49 C. After stirring at ambient temperaturefor 90 min, sodium hydride (9.0 g of a 60% oil dispersion, 0.225 mol)was added portion wise over 20 min and the reaction temperature rose to38° C. Gas evolution was also observed. After stirring at ambienttemperature for 40 min, a solution of ethyl4-[(4-fluorophenyl)sulfonyl]-1-(2-methoxyethyl)piperidine-4-carboxylate(56 g, 0.15 mol) in dimethylsulfoxide (20 mL) was added over 10 mins asthe reaction rose to 38° C. The reaction was stirred at ambienttemperature for 30 min. The slurry was slowly poured into ice water (1.1L) and then extracted with hexanes (300 mL) two times followed by adiethyl ether extraction (200 mL). The aqueous layer was chilled to 5°C. and the pH adjusted to 7 with concentrated hydrochloric acid. Theaqueous solution was extracted with methylene chloride (150 mL) untilthere was no UV activity in the extract. The combined methylene chlorideextracts were washed with saturated sodium chloride solution, dried overNa₂SO₄, filtered, and concentrated in vacuo. The solid wasrecrystallized from methanol (200 mL) to give the butyric acid as awhite solid (34.8 g, 51%). LCMS_(m/z)=458 [M+H]⁺.

Part B. In dry equipment under nitrogen, the butyric acid from Part A(19.19 g, 42.0 mmol) was dissolved in dry dimethylformamide (100 mL) andthe remaining reagents were added to the solution in the followingorder: N-hydroxybenzotriazole hydrate (8.5 g, 63.0 mmol), triethylamine(11.7 mL, 84.0 mmol),

4-(trifluoromethoxy)benzamidoxime (13.9 g, 63.0 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16.1 g,84.0 mmol). After 24 hr at 70° C., the reaction was concentrated invacuo. The residue was taken up in ethyl acetate, washed with water,saturated NaHCO₃, saturated sodium chloride solution, dried over Na₂SO₄,filtered, and concentrated in vacuo. The solid was recrystallized frommethanol (35 mL) to give the oxadiazole as an off white solid (17.86 g,66%). LCMS_(m/z)=642 [M+H]⁺.

Part C. A slurry of the oxaziazole from Part B (16.9 g, 26.4 mmol), 2.5Nsodium hydroxide (31.6 mL, 79.1 mmol) and sodium hydroxide (4.22 g,105.5 mmol) in isopropanol (30 mL) were stirred at 70° C. for 7 hr. Theheat was removed and the reaction diluted with water (150 mL) andchilled to 5° C. The pH was adjusted to 7 with concentrated hydrochloricacid. The solids were filtered, washed with hexanes, and dried in vacuoto give the carboxylic acid as a white solid (15.78 g, 98%).LCMS_(m/z)=614 [M+H]⁺.

Part D. In dry equipment under nitrogen, the carboxylic acid from Part C(15.7 g, 25.6 mmol) was dissolved in dry dimethylformamide (70 mL) andthe remaining reagents were added to the solution in the followingorder: N-hydroxybenzotriazole hydrate (5.19 g, 38.4 mmol), triethylamine(10.7 mL, 76.8 mmol), O-(tetrahydro-2H-pyran2-yl)hydroxylamine (5.99,51.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (10.8 g, 56.3 mmol). After 12 hr at 40° C., the reactionwas concentrated in vacuo. The residue was taken up in ethyl acetate,washed with water, saturated NaHCO₃, saturated sodium chloride solution,dried over Na₂SO₄, filtered, and concentrated in vacuo. Chromatography(on silica, ethyl acetate/hexanes) provided the THP hydroxamate as awhite foam (14.94 g, 82%). LCMS_(m/z)=713 [M+H]⁺.

Part E. To the THP hydroxamate from Part D (14.88 g, 20.9 mmol) wasadded 4N HCl dioxane solution (52 mL, 209.0 mmol) and methanol (5.2 mL).The slurry became very thick. Dioxanes (50 mL) and diethyl ether (100mL) were added to facilitate stirring. After 1 hr at ambient temperaturethe reaction was filtered under nitrogen. The solids were washed withacetonitrile (100 mL) under nitrogen and dried in vacuo over phoshoruspentoxide to give the title compound as a white solid (13.25 g, 95%).HRMS (ES+) M+H⁺ calculated for C₂₇H₃₁N₄O₈S₁F₃: 629.1893, found 629.1913.

Example 43 Preparation of4-({4-[3-(1,3-benzoxazol-2-ylthio)propoxy]phenyl]sulfonyl)-N-hydroxy-1-(2-methoxyethyl)piperidine-4-carboxamidehydrochloride

Part A. A solution of 1-benzyl 4-tert-butyl4-[(4-fluorophenyl)sulfonyl]piperidine-1,4dicarboxylate (16.0 g, 33.5mmol) in methanol/tetrahydropyran was hydrogenated for 1 hr at 5 psi inthe presence of 5% Pd/C. The solution was filtered to remove thecatalyst and concentrated in vacuo. 11.0 g (95% yield) of the amine wasobtained as a white solid.

Part B. The solution of the amine of Part A (11.0 g, 32.1 mmol) inN,N-dimethylformamide (100 mL) was cooled to 0° C. on an ice bath.Potassium carbonate (13.3 g, 96.4 mmol) and 2-bromoethylmethyl ether(7.54 mL, 80.2 mmol) were added to the chilled solution. The solutionwas stirred for 72 hr at ambient temperature and partitioned betweenethyl acetate and water. The organic layer was washed with water andsaturated sodium chloride and dried over sodium sulfate. 14.5 g of thedesired alkylated amine was obtained as an orange oil by concentrationin vacuo.

Part C. To a solution of propanediol (10.44 mL, 144 mmol) in1-methyl-2-pyrrolidinone (40 mL) cooled to 0° C. was added sodiumhydride (60% suspension in mineral oil, 3.85 g, 96.3 mmol). Thealkylated amine from Part B (14.5 g, 32.1 mmol) was dissolved into1-methyl-2-pyrrolidinone (50 mL) and added dropwise to the cooledsolution. The solution was stirred at ambient temperature for 1 hr. Thereaction was quenched by adding water and partitioned between ethylacetate and water. The organic layer was washed with water and saturatedsodium chloride and dried over sodium sulfate. The desired alcohol wasobtained as an orange oil by concentration in vacuo. MS(CI) MH⁺calculated for C₂₂H₃₅NO₇S: 457, found 457.

Part D. To a solution of the alcohol of Part C (32.1 mmol) in methylenechloride (100 mL) was added triethylamine (4.92 mL, 35.3 mmol). Thesolution was cooled to 0° C. and methanesulfonyl chloride (2.56 mL, 33.0mmol) was added dropwise. After 1 hr the reaction was concentrated invacuo. The residue was dissolved into ethyl acetate and washed withwater, saturated sodium bicarbonate and saturated sodium chloride anddried over sodium sulfate. The solution was concentrated in vacuo toprovide 17.5 g of the desired mesylate. MS(CI) MH⁺ calculated forC₂₃H₃₇NO₉S₂: 536, found 536.

Part E. To a solution of 2-mercaptobenzoxazole (4.86 g, 32.1 mmol) inN,N-dimethylformamide (30 mL) cooled to 0° C. was added sodium hydride(60% suspension in mineral oil, 1.54 g, 38.5 mmol). After 30 min themesylate of Part D (17.5 g, 32.1 mmol) in N,N-dimethylformamide (30 mL)was added dropwise. The solution was heated at 60° C. for 4 hr and at45° C. for 18 hr. The solution was returned to ambient temperature andpartitioned between ethyl acetate and water. The organic layer waswashed with water and saturated sodium chloride and dried over sodiumsulfate. Chromotography (ethyl acetate, on silica) provided themercaptobenzoxazole as a colorless oil (7.3 g, 39% yield over foursteps). MS(CI) MH⁺ calculated for C₂₉H₃₈N₂O₇S₂: 591, found 591.

Part F. To a solution of the mercaptobenzoxazole of Part E (7.3 g, 12.4mmol) was added trifluoroacetic acid (20 mL) and the solution stirredfor 3 hr. The solution was concentrated in vacuo and azotroped withtoluene to provide the acid as an oil. The material was carried onwithout additional purification. MS(CI) MH⁺ calculated for C₂₅H₃₀N₂O₇S₂:535, found 535.

Part G. To a solution of the acid of Part F (12.4 mmol) inN,N-dimethylformamide (50 mL) were added 1-hydroxybenztriazole (2.01 g,14.9 mmol), 4-methylmorpholine (6.82 mL, 62 mmol) andtetrahydropyranylamine (2.18 g, 18.6 mmol). After 30 min1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.33 g,17.4 mmol) was added. The solution was heated to 65° C. for 2 hr. Thesolution was partitioned between ethyl acetate and water. The organiclayer was washed with water and saturated sodium chloride and dried oversodium sulfate. Chromotography (ethyl acetate/methanol, on silica)provided the protected hydroxamate as a colorless oil (3.9 g, 50%yield). MS(CI) MH⁺ calculated for C₃₀H₃₉N₃O₈S₂: 634, found 634.

Part H. To a solution of the protected hydroxamate of Part G (3.9 g, 6.2mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in1,4-dioxane (10 mL). The reaction was complete after 1 hr. The solutionwas concentrated in vacuo. The residue was purified via reverse phasechromatography (acetonitrile/water, on silica) to provide the titlecompound as a white solid (1.49 g, 41% yield). MS(CI) MH⁺ calculated forC₂₅H₃₁N₃O₇S₂: 550, found 550. HRMS calculated for C₂₅H₃₁N₃O₇S₂:550.1682, found 550.1668. Analytical calculation forC₂₅H₃₁N₃O₇S₂.HCl.H₂O: C, 49.70; H, 5.67; N, 6.96; S, 10.62; Cl, 5.87.Found: C, 49.91; H, 6.03; N, 6.74; S, 10.75; Cl, 6.35.

Example 44 Preparation of

Part A. Preparation of:

To a solution of 3-(3-bromophenyl)propionic acid (15.0 g, 65.5 mmol) inanhydrous THF (200 mL) at 5° C. was added, via addition funnel, 1.0 MBH₃.THF (200 mL, 200 mmol). The reaction temperature was kept below 14°C. during the addition of the BH₃.THF. After all the BH₃.THF was added,the reaction was refluxed for 22 hr and then quenched with water (100mL) and 1N HCl (300 mL). The solution was saturated with sodium chlorideand extracted with ethyl acetate (3×300 mL). The organic extract waswashed with brine, dried over magnesium sulfate, and concentratedproviding 14.4 g (100%) of crude alcohol as a colorless oil. NMR(CDCl₃)δ 1.82-1.89 (m, 2H), 2.67 (t, 2H), 3.64 (t, 2H), 7.11-7.15 (m, 1H),7.29-7.31 (m, 1H), 7.34 (s, 1H).

Part B. Preparation of:

In a flask were combined the alcohol from Part A (65.5 mmol), phenylboronic acid (12.0 g, 98.2 mmol), palladium tetrakistriphenylphosphine(3.8 g, 3.3 mmol), 2M cesium carbonate (98 mL, 196 mmol) anddimethoxyethylether (100 mL). The mixture was stirred vigorously undernitrogen at reflux overnight. The reaction was cooled to ambienttemperature, poured into water (300 mL) and extracted 3 times with ethylacetate. The combined organic extracts were washed with brine and driedover magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane)provided the coupled product as a golden oil (1.95 g, 86.0%). NMR(CDCl₃)δ 1.91-1.98 (m, 2H), 2.77 (t, 2H), 3.71 (t, 2H), 7.19 (d, 1H), 7.31-7.38(m, 2H), 7.41-7.45 (m, 4H), 7.58 (d, 2H).

Part C. Preparation of:

To a solution of the alcohol from Part B (11.9 g, 56.1 mmol) inanhydrous dimethylformamide (56 mL) at 0° C. was added 60% sodiumhydride (2.55 g, 63.8 mmol) in portions. After completion of theaddition, the reaction was stirred at 0° C. for 15 min then ambienttemperature for 15 min. The reaction was cooled to 0° C. and ethyl4-[(4-fluorophenyl)sulfonyl]-1-(2-methoxyethyl)piperidine-4-carboxylate(19.0 g, 51 mmol) in anhydrous dimethylformamide (60 mL) was addedslowly. Upon completion of addition, the ice bath was removed and thereaction stirred at ambient temperature overnight. Reaction was pouredinto water (1 L) and extracted with ethyl acetate (800 mL). The combinedorganics were washed with water (2×500 mL) and brine and dried overmagnesium sulfate. Concentration gave 34.4 g of crude material. Thismaterial was used without purification.

Part D. Preparation of:

The impure ester of Part C (34.4 g, 51 mmol theoretical) was hydrolyzedin 41 mL of ethanol, 41 mL of 1,4-dioxane and 26.5 mL of 6 N NaOH at 60°C. The solution was poured into water and extracted with ether to removecolor. Acidification with 1N HCl caused precipitation of the acid whichwas collected by filtration and washed with water, ethyl acetate andhexane then dried under high vacuum yielding the acid as an off whitesolid (18.8 g, 68.6% yield). NMR (CD₃OD w/K₂CO₃) δ 1.98 (t, 2H),2.07-2.19 (m, 4H), 2.32 (d, 2H), 2.48 (t, 2H), 2.85-2.95 (m, 4H), 3.25(s, 3H), 4.06 (t, 2H), 7.04 (d, 2H), 7.20 (d, 1H), 7.27-7.48 (m, 5H),7.54 (d, 2H), 7.78 (d, 2H). ESMS m/z=538 (M+H)⁺.

Part E. Preparation of:

To the acid of Part D (12.7 g, 23.6 mmol), HOBt (5.42 g, 35.4 mmol), EDC(6.30 g, 3.30 mmol) in a flask under N₂ was added 70 mL anhydrous DMF.The mixture was heated to 60° C. and triethylamine (9.85 mL, 70.8 mmol)was added. After heating at 60° C. for 1 hr, THP-hydroxylamine (4.14 g,35.4 mmol) was added. The solution was stirred for 16.5 hr at 60° C. Thesolution was partitioned between ethyl acetate (300 mL) and water (500mL). The organic layer was washed with brine and dried over magnesiumsulfate. Concentration provided the protected hydroxamate as an oil(14.86 g, 98.7%). NMR(CDCl₃) δ 1.55-1.90 (m, 6H), 2.09-2.27 (m, 8H),2.50 (t, 2H), 2.87 (t, 2H), 2.90-2.98 (m, 2H), 3.32 (s, 3H), 3.42 (t,2H), 3.7.1 (d, 1H), 3.98 (d, 1H), 4.03 (t, 2H), 4.99 (s, 1H), 6.97 (d,2H), 7.19 (d, 1H), 7.30-7.46 (m, 6H), 7.57 (d, 2H), 7.77 (d, 2H), 9.42(s, 1H). ESMS m/z=637 (M+H)⁺.

Part F. Preparation of:

To the product from Part E (14.7 g, 23.1 mmol) in methanol (23 mL) and1,4-dioxane (23 mL) was added 4M hydrochloric acid in 1,4-dioxane (23mL) and after stirring 1 hr, material dripped in to stirring IPA, letstand overnight. Collection of solid under N₂ followed by washing with[PA and hexane then drying on high vacuum over P₂O₅ provided 12.5 g(91.8%) of the title compound as a hydrochloric acid salt that wascolorless. NMR(DMSO) δ 2.05-2.25 (m, 4H), 2.74, (t, 2H), 2.81 (t, 2H),3.18-3.26 (m, 4H), 3.39 (s, 3H), 3.51-3.61 (m, 4H), 4.09 (t, 2H), 7.15(d, 2H), 7.22 (d, 1H), 7.29-7.49 (m, 6H), 7.58 (d, 2H), 7.45 (d, 2H).ESMS m/z=553 (M+H)⁺. HRMS calcd. for C₃₀H₃₅N₂O₅S H: 553.2369 (M+H)⁺.Found: 553.2372.

Example 45 Preparation of

Part A. Preparation of:

In a flask were combined the 3-bromophenethyl alcohol (17.5 g, 87.1mmol), phenyl boronic acid (12.7 g, 104.5 mmol), palladiumtetrakistriphenylphosphine (2.0 g, 1.74 mmol), 2M cesium carbonate (105mL, 210 mmol) and dimethoxyethylether (105 mL). Mixture stirredvigorously under nitrogen at reflux overnight. After cooling to ambienttemperature, poured mixture into water (400 mL) and extracted with ethylacetate (2×400 mL). Combined organics were washed with brine and driedover magnesium sulfate. Silica gel chromotography (ethyl acetate/hexane)provided the coupled product as a crystalline solid (15.04 g, 87.3%).NMR(CDCl₃) δ 2.95 (t, 2H), 3.93 (q, 2H), 7.19-18 (m, 2H), 7.31-7.51 (m,5H), 7.58 (d, 2H). GCMS EI+ 198 (M+).

Part B. Preparation of:

To a solution of the alcohol from Part A (14.9 g, 75.2 mmol) inanhydrous dimethylformamide (70 mL) at 0° C. was added 60% sodiumhydride (3.0 g, 75.2 mmol) in portions. After completion of theaddition, the reaction was stirred at 0° C. for 30 min. ethyl4-[(4-fluorophenyl)sulfonyl]-1-(2-methoxyethyl)piperidine-4-carboxylate(33.6 g, 90.2 mmol) in anhydrous dimethylformamide (50 mL) at 5° C. wasadded slowly. Upon completion of addition let reaction slowly warm upovernight. Reaction was poured into water (700 mL) and extracted withethyl acetate (3×500 mL). The combined organics were washed with brineand dried over sodium sulfate. Concentration gave 50.6 g of crudematerial. This material was used without purification. ESMS m/z=552(M+H)⁺.

Part C. Preparation of:

The impure ester of Part B (75.2 mmol theoretical) was hydrolyzed in 75mL of ethanol, 75 mL of 1,4-dioxane and 50 mL of 6 N NaOH at 60 C for2.5 hr. The solution was poured into water and extracted with ether toremove color. Acidification with 1N HCl caused precipitation of the acidwhich was collected by filtration and washed with water, ethyl acetateand diethyl ether then dried under high vacuum yielding the acid as awhite solid (31.7 g, 80.6% yield). ESMS m/z=524 (M+H)⁺. HRMS calcd. forC₂₉H₃₄NO₆S: 524.2101 (M+H)⁺. Found: 524.2075.

Part D. Preparation of:

The acid of Part C (31.6 g, 60.4 mmol), HOBt (13.9 g, 90.6 mmol), EDC(16.2 g, 84.6 mmol), triethylamine (25.2 mL, 181 mmol) andTHP-hydroxylamine (10.6 g, 90.6 mmol) were stirred in anhydrousdimethylformamide (200 mL) under N₂ at 60° C. overnight. After coolingto room temperature solution was poured into 1.6 L of ice water andextracted with ethyl acetate (2×1 L). The organic layer was washed withbrine and dried over sodium sulfate. Silica gel chromatography (2.0M NH₃in MeOH/ethyl acetate/hexane) gave the desired product as a colorlessfoam (30.89 g, 82%). ESMS m/z=623 (M+H)⁺. HRMS calcd. for C₃₄H₄₃N₂O₇S:623.2786 (M+H)⁺. Found: 623.2793.

Part E. Preparation of:

To the product from Part D (30.7 g, 49.3 mmol) in methanol (49 mL) and1,4-dioxane (49 mL) was added 4N HCl in dioxane (50 mL). Materialconcentrated after 1 hr and crystallized from methanol providing thedesired product as a colorless crystalline solid (25.6 g, 90.2%). ESMSm/z=539 (M+H)⁺. HRMS calcd. for C₂₉H₃₅N₂O₆S: 539.2210 (M+H)⁺. Found:539.2187.

Example 46 Preparation of

Part A. Preparation of:

To a solution of the alcohol from Example 38, Part B (12.0 g, 56.1 mmol)in anhydrous dimethylformamide (50 mL) at 0° C. was added 60% sodiumhydride (2.58 g, 64.5 mmol) in portions. After completion of theaddition, the reaction was stirred at 0° C. for 15 min then ambienttemperature for 15 min. The reaction was cooled to 0° C. and ethyl1-ethyl-4-[(4-fluorophenyl]sulfonyl]piperidine-4-carboxylate (17.7 g,51.6 mmol) in anhydrous dimethylformamide (60 mL) was added slowly. Uponcompletion of addition, ice bath was removed and reaction stirred atambient temperature overnight. Reaction was poured into water andextracted with ethyl acetate 2 times. The combined organics were washedwith water 2 times and brine and dried over sodium sulfate.Concentration gave 34.4 g of crude material. This material was usedwithout purification. ESMS m/z=536 (M+H)⁺.

Part B. Preparation of:

The impure ester of Part A (51.6 mmol theoretical) was hydrolyzed in 50mL of ethanol, 50 mL of 1,4-dioxane and 34.4 mL of 6 N NaOH at 60° C.After cooling to room temperature, the solution was poured into water(500 mL) and extracted with ether (2×250 mL) to remove color.Acidification with 1N HCl caused precipitation of the acid which wascollected by filtration and washed with water, ethyl acetate and hexanethen dried under high vacuum yielding the acid as an off white solid(18.4 g, 70% yield). ESMS m/z=508 (M+H)⁺. HRMS calcd. for C₂₉H₃₄NO₅S H:508.2152 (M+H)⁺. Found: 508.2176.

Part C. Preparation of:

The acid of Part B (18.0 g, 35.4 mmol), HOBt (8.12 g, 53.1 mmol), EDC(9.47 g, 49.6 mmol), triethylamine (14.8 mL, 106.2 mmol) andTHP-hydroxylamine (6.21 g, 53.1 mmol) were stirred in anhydrousdimethylformamide (110 mL) under N₂ at 60° C. overnight. After coolingto room temperature, the solution was poured into water (600 mL) andextracted with ethyl acetate. The organic layer was washed with waterand brine and dried over sodium sulfate. Silica gel chromatography (2.0MNH₃ in MeOH/ethyl acetate/hexane) gave the desired product as acolorless foam (11.0 g, 51%). ESMS m/z=607 (M+H)⁺. HRMS calcd. forC₃₄H₄₃N₂O₆S: 607.2836 (M+H)⁺. Found: 607.2829

Part D. Preparation of:

To the product from Part C (10.8 g, 17.8 mmol) in methanol (18 mL) and1,4-dioxane (18 mL) was added 4M hydrochloric acid in 1,4-dioxane (18mL) and after stirring 1 hr, material concentrated. Co-crystallized withanother batch from MeOH/4N HCl/dioxane. Collection of solid followed bywashing with methanol then drying on high vac provided 11.51 g (88%) ofthe title compound as a hydrochloric acid salt that was colorless. ESMSm/z=523 (M+H)⁺. HRMS calcd. for C₂₉H₃₅N₂O₅S H: 523.2261 (M+H)⁺. Found:523.2224.

Example 47 Preparation of4-[(4-{3-[4-(2,4-difluorophenyl)thien-2-l]propoxy}phenyl)sulfonyl]-N-hydroxy-1-(2-methoxyethyl)piperidine-4-carboxamidehydrochloride.

Part A. A round bottom flask was charged with 4-bromo-2-thiophenecarboxaldehyde (Aldrich, 55.8 g, 292 mmol), 2,4-difluorophenyl boronicacid (Aldrich, 60.0 g, 380 mmol), tetrakis-triphenylphosphine palladium(Aldrich, 16.9 g, 14.6 mmol), 2 M Na₂CO₃._(qa) (190 ml, 380 mmol), andethylene glycol-dimethyl ether (Aldrich, 500 ml). The reaction washeated to 80° C. and stirred for 5 hr. The reaction suspension was thenpoured into a mixture of methylene chloride (500 ml) and ice water (500ml). The organic layer was separated and washed with water (2×200 ml)and brine (1×300 ml) then dried over Na₂SO₄ and concentrated to affordthe thiophene phenyl adduct as a brown oil. Silica gel purification(hexanes/ethyl acetate) yielded a white solid (34.2 g, 52% yield). ¹HNMR showed the desired compound.

Part B. A solution of triethyl phosphonoacetate (Aldrich, 24.2 g, 108mmol) in tetrahydrofuran (100 ml) was cooled to −78° C. A 1.6 Mn-butyllithium solution in hexanes (68 ml, 108 mmol) was slowly drippedin then the reaction stirred for 30 min at −78° C. A solution of thethiophene phenyl carboxaldehyde product from Part A in tetrahydrofuran(100 ml) was slowly dripped in. The dry ice bath was removed and thereaction stirred as it came to ambient temperature overnight. Themixture was diluted with water (200 ml) to quench. The organic layer wasseparated and washed with water (2×200 ml) and brine (1×300 ml) thendried over Na₂SO₄ and concentrated to afford a tan solid. This solid wasrecrystallized from warm methanol to yield a light yellow solid (16.1 g,56% yield). ¹H NMR showed the desired compound.

Part C. A solution of the ethyl ester olefin of Part B (16 g, 54.4 mmol)in methylene chloride was cooled to 0° C. A 1.0 M solution of lithiumaluminum hydride was dripped in slowly, then the reaction continuedstirring for 45 min at 0° C. A saturated solution of NH₄Cl._(qa) wasdripped in to quench, followed by a solution of sodium, potassiumtartrate_(aq) (10 ml). After stirring for 30 min, Na₂SO₄ (40 g) wasadded. The mixture was filtered and concentrated to afford a yellow oil(16.8 g, 100⁺% yield). ¹H NMR showed the desired compound along withimpurities.

Part D. A hydrogenation flask was charged with the crude hydroxy olefinresidue from Part C (˜54.4 mmol) was dissolved in tetrahydrofuran (125ml) and methanol (20 ml). Nitrogen gas was bubbled through for 15 minthen 10% Pd/C catalyst (Aldrich, 50% water, 2.7 g) was added. Ahydrogenation head was attached and the vessel was purged with nitrogen(3×), followed by hydrogen (3×). The vessel was left at 50 psi ofhydrogen. After 1 hr of stirring, the reaction was complete by LCMS. Themixture was filtered through a Celite pad and concentrated to afford ablack oil that was purified on silica gel (hexanes/ethyl acetate).Collected fractions gave the product as a clear oil (8.6 g, 62%yield).). ¹H NMR showed the desired compound.

Part E. The saturated alcohol from Part D (7.6 g, 30.0 mmol) wasdissolved in dimethylsulfoxide (60 ml). Sodium hydride (Aldrich, 60% inoil dispersion, 1.3 g, 32.6 mmol) was added portion wise over 30 min.After stirring for 1 hr, the aryl-fluoride, SC 84087, was added and thereaction was stirred overnight at ambient temperature. The reaction wasquenched with saturated NH₄Cl_(aq) (100 ml) then extracted with ethylacetate (3×-125 ml). The combined organics were washed with water(2×-200 ml) and brine (1×-200 ml) then dried over Na₂SO₄ filtered andconcentrated to a brown oil. The residue was purified on silica gel(hexanes/ethyl acetate) to afford the product as a tan solid (14.0 g,81% yield).). ¹H NMR showed the desired compound at 90% purity.

Part F. The t-butyl ester from Part E (9.5 g, 15.0 mmol) was dissolvedin methylene chloride (30 ml) after which, trifluoroacetic acid(Aldrich, 30 ml) was added. The reaction stirred for 4 hr then wasconcentrated to one-third volume via a nitrogen stream. The slightlyviscous residue was then dripped into stirring diethyl ether to form asolid that was filtered and dried to give the product as a tan solid(6.9 g, 66% yield). ¹H NMR showed the desired compound.

Part G. To a solution of the carboxylic acid of Part F (6.9 g, 9.9 mmol)in N,N-dimethylformamide (20 ml) was added triethylamine (Aldrich, 4.2ml, 30.0 mmol) followed by N-hydroxybenzotriazole hydrate (Aldrich, 2.7g, 20.0 mmol), O-(tetrahydro-2H-pyran-2-yl) hydroxylamine (2.34 g, 20.0mmol), and, lastly, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (Sigma, 4.18 g, 21.8 mmol). The reaction stirred at roomtemperature for 18 hr. The mixture was diluted with water (30ml) thenextracted with ethyl acetate (3×-100 ml). The organics were combined andwashed with saturated NaHCO₃. (3×-100 ml), water (2×-100 ml), and brine(1×-150 ml). After drying over Na₂SO₄, the mixture was filtered andconcentrated for a tan oil. The oil was tritiated with ethanol (3×) andmethanol (3×) to afford a tan oil (8.1 g, 100⁺% yield). ¹H NMR showedthe desired compound with trace impurities.

Part H. The crude protected hydroxamic acid of Part G (˜9.9 mmol) wasslurried in methanol (4 ml) and stirred with 4 N HCl in dioxane (20 ml)for 1 hr. The solvent volume was reduced in half then diethylether wasadded, providing a gummy solid that was purified by Reverse Phase LC(C₁₈, acetonitrile/water). The resulting partial TFA salt was dissolvedin 4 N HCl in dioxane (20 ml) and stirred for 1 hr. The solvent volumewas again reduced in half then diethyl ether was added, providing awhite solid. The solid was collected and dried to afford the desiredhydrochloride salt as a white powder (3.35 g, 54% yield). ¹H NMR showedthe desired compound.

Example 48 Preparation of

Part A. Preparation of:

A mixture of lithium chloride (1.71 g, 40.3 mmol),trifluoromethoxy-benzonitrile (5.00 g, 26.7 mmol), and sodium azide(1.75 g, 26.7 mmol) in 2-methoxyethanol (26 mL) under an N₂ atmospherewas refluxed for 4 hr. The ambient mixture was poured into a mixture ofice (84 g) and concentrated HCl (8.4 mL) and stirred until the icemelted. The white solid was collected by filtration, washed with water,and dried for 2 hr in a 40° C. vacuum oven to produce the tetrazole inthe form of an off white solid (4.86 g, 79% yield). MS MH⁺ calcd. forC₈H₆N₄OF₃ 231, found 231.

Part B. Preparation of:

A solution of the tetrazole of Part A (2.00 g, 8.69 mmol) in NMP (12 mL)was added dropwise to an ambient mixture of 95% sodium hydride (0.438 g,18.2 mmol) in NMP (12 mL) under an N₂ atmosphere. After an 1 hr ofstirring, 2-(3-chloropropoxy)tetrahydro-2H-pyran (1.58 mL, 9.56 mmol)was added dropwise. The mixture was stirred at ambient temperature for18 hr and then at 70° C. for 2 hr. The mixture was diluted with asolution of water (200 mL) and saturated NaHCO₃ (100 mL), and extractedwith ethyl acetate (3×100 mL). The organic layer was washed with water(2×100 mL) and brine (100 mL), dried over MgSO₄, and concentrated invacuo to produce a yellow liquid. Flash chromatography purification(ethyl acetate-hexane/silica gel) provided the pyran in the form of awhite solid (1.46 g, 45% yield). Anal. Calcd. for C₁₆H₁₉N₄O₃F₃: C,56.34; H, 5.98; N, 7.73; S, 4.42. Found C, 56.13; H, 6.08; N, 7.65; S,4.75.

Part C. Preparation of:

To an ambient solution of the pyran of Part B (1.40 g, 3.76 mmol) inMeOH (13.5 mL) was added a solution of acetyl chloride (0.896 mL, 13.1mmol) in MeOH (13.5 mL). After 15 min, the solution was concentrated invacuo to provide the alcohol in the form of a solid (1.02 g, 94% yield).MS MH⁺ calcd. for C₁₁H₁₂N₄O₂F₃ 289, found 289.

Part D. Preparation of:

To an ambient mixture of 95% sodium hydride (0.110 g, 3.58 mmol) in NMP(2.5 mL) under an N₂ atmosphere was added dropwise a solution of thealcohol of Part C (1.00 g, 3.47 mmol) in NMP (3.2 mL), and then themixture was heated at 55° C. for 30 min. A solution of ethyl4-[(4-fluorophenyl)sulfonyl]-1-(2-methoxyethyl)piperidine-4-carboxylate(1.22 g, 3.27 mmol) in NMP (3.2 mL) was added dropwise to the 55° C.reaction mixture. After 1 hr at 55° C., the ambient mixture was dilutedwith a solution of water (600 mL) and NaHCO₃ (100 mL), and extractedwith ethyl acetate (3×200 mL). The organic layer was washed with water(2×50 mL) and brine (150 mL), dried over MgSO₄, and concentrated invacuo to form a yellow oil (1.96 g). Flash chromatography purification(MeOH-EA/silica gel) provided the sulfone in the form of a yellow oil(1.48 g, 70% yield). MS MH⁺ calcd. for C₂₈H₃₅N₅O₇SF₃ 642, found 642.

Part E. Preparation of:

A mixture of the sulfone of Part D (1.44 g, 2.24 mmol) and 50% aqueousNaOH (1.08 g, 22.4 mmol) in a solution of THF (23 mL) and EtOH (11 mL)was stirred at ambient temperature for 3 hr and then 60° C. for 15 min.The mixture was concentrated in vacuo, diluted with a solution ofacetonitrile and water, acidified to a pH of approximately 2 withconcentrated HCl, and concentrated in vacuo to provide the acid(containing NaCl) as a crude tan foam (2.77 g). MS MH⁺ calcd. forC₂₆H₃₁N₅O₇SF₃ 614, found 614.

Part F. Preparation of:

A mixture of the crude acid of Part E (2.24 mmol), 1-hydroybenzotriazolehydrate (0,534 g, 3.95 mmol), triethylamine (3.62 mL, 25.9 mmol),O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.542 g, 4.63 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.888 g,4.63 mmol) in DMF (23 mL) under an N₂ atmosphere was stirred at ambienttemperature for 40 hr. The mixture was diluted with water (400 mL) andextracted with ethyl acetate (3×100 mL). The organic layer was washedwith water (2×100 mL) and brine (100 mL), dried over MgSO₄, andconcentrated in vacuo to form a white foam (1.37 g). Chromatographypurification (MeOH-EA/silica gel) produced the O-protected hydroxamatein the form of a white foam (1.04 g, 65% based on the ester of Part 1D).MS MH⁺ calcd. for C₃₁H₄₀N₆O₈F₃S 713, found 713. Anal. Calcd. forC₃₁H₃₉N₆O₈F₃S: C, 52.24; H, 5.52; N,11.79. Found C, 52.47; H, 5.73; N,11.64.

Part G. Preparation of:

A solution of the O-protected hydroxamate of Part F (0.960 g, 1.35 mmol)and acetyl chloride (0.493 g, 6.53 mmol) in methanol (15 mL) was stirredat ambient temperature for 1 hr. The solution was concentrated in vacuoto a white solid. The solid was triturated with ether and concentratedin vacuo to provide the title compound in the form of a white solid(0.66 g, 74% yield). Anal. Calcd. for C₂₆H₃₁N₆O₇F₃S¹HCl: C, 46.95; H,4.85; N, 12.64; Cl, 5.33; S, 4.82. Found C, 46.59; H, 5.07; N, 12.64;Cl, 5.36; S, 5.20. MS MH⁺ calcd. for C₂₆H₃₂N₆O₇F₃S 629. found 629.

Example 49 Preparation of

Part A Preparation of:

To an ambient mixture of 95% sodium hydride (0.397 g, 16.5 mmol) in NMP(7 mL) under an N₂ atmosphere was added dropwise a solution of thealcohol of Part C of Example 48 (3.44 g, 11.9 mmol) in NMP (7 mL). Themixture was then stirred at ambient temperature for 45 min. The ethyl1-cyclopropyl-4-[(4-fluorophenyl)sulfonyl]piperidine-4-carboxylate (4.00g, 11.3 mmol) was added in one portion, and the mixture was heated to60° C. After heating for 24 hr at 60° C. and adding 2 more portions of95% sodium hydride (0.10 g, 4.0 mmol and 0.08 g, 3.0 mmol), the mixturewas diluted with water (300 mL) and extracted with ethyl acetate (3×100mL). The organic layer was washed with water (2×100 mL) and brine (100mL), dried over MgSO₄, and concentrated in vacuo to form a yellow oil(5.81 g). Flash chromatography purification (Hexane-EA/silica gel)produced the sulfone in the form of a yellow oil (3.10 g, 44% yield).The proton NMR (CDCl₃) spectrum was consistent with the desired sulfoneproduct.

Part B. Preparation of:

A mixture of the sulfone of Part A (3.00 g, 4.81 mmol) and 50% aqueousNaOH (3.85 g, 48.1 mmol) in a solution of THF (50 mL) and EtOH (24 mL)was stirred for 2.5 hr at 60° C. The mixture was concentrated in vacuo,diluted with a solution of acetonitrile and water, acidified to a pH ofapproximately 2 with concentrated HCl, and concentrated in vacuo. Thecrude acid was purified by reverse phase HPLC (H₂O—CH₃CN) to produce theacid in the form of a white solid (1.86 g, 55% yield). MS MH⁺ calcd. forC₂₆H₂₉N₅O₆F₃S 596, found 596.

Part C. Preparation of:

A mixture of the acid of Part B (1.80 g, 2.85 mmol),1-hydroybenzotriazole hydrate (0.679 g, 5.02 mmol), triethylamine (4.61mL, 33.1 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.692 g, 5.91mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(1.13 g, 5.91 mmol) in DMF (29 mL) under an N₂ atmosphere was stirred atambient temperature for 24 hr and 57° C. for 6.5 hr. The mixture wasconcentrated in vacuo, diluted with water (300 mL), and extracted withethyl acetate (3×100 mL). The organic layer was washed with water (2×100mL) and brine (100 mL), dried over MgSO₄, and concentrated in vacuo toform a yellow oil (1.80 g). Flash chromatography purification(MeOH—CH₂Cl₂/silica gel) produced the O-protected hydroxamate in theform of a white foam (0.89 g, 45% yield). MS MH⁺ calcd. forC₃₁H₃₈N₆O₇F₃S 695, found 695. Anal. Calcd. for C₃₁H₃₇N₆O₇F₃S: C, 53.59;H, 5.37; N,12.10; S, 4.62. Found C, 53.30; H, 5.43; N, 12.05; S, 4.73.

Part D. Preparation of:

A solution of the O-protected hydroxamate of Part C (0.870 g, 1.25 mmol)and acetyl chloride (0.456 g, 6.04 mmol) in methanol (14 mL) was stirredat ambient temperature for 30 min. The mixture was poured into diethylether (250 mL). The white solid was isolate by filtration and dried in a40° C. vacuum oven to produce the title compound in the form of a whitesolid (0.56 g, 69% yield). MS MH⁺ calcd. for C₂₆H₃₀N₆O₆F₃S 611, found611.

Example 50 Preparation of

Part A. Preparation of:

To a solution of the alcohol from Part B of Example 38 (3.65 g, 17.0mmol) in anhydrous dimethylformamide (17 mL) at 5° C. was added 60%sodium hydride (0.77 g, 19.3 mmol) in portions. After completion of theaddition, the reaction was stirred at 5° C. for 15 min and then atambient temperature for 15 min. The reaction was cooled to 5° C. andethyl4-[(4-fluorophenyl)sulfonyl]-1-(2-methoxyethyl)piperidine-4-carboxylate(6.0 g, 16.1 mmol) in anhydrous dimethylformamide (15 mL) was addedslowly. Reaction stirred at room temperature for 2 hr, then was dilutedwith water (250 mL) and extracted with ethyl acetate (3×150 mL). Thecombined organics were washed with brine and dried over magnesiumsulfate. Silica Gel chromatography (ethyl acetate/hexane) gave theproduct as a colorless oil (8.06 g, 88%). NMR(CDCl₃) δ 1.20-1.26 (m,3H), 1,88-2.02 (m, 2H), 2.06-2.27 (m, 4H), 2.43 (d, 2H), 2,53 (bs, 2H),2.78 (t, 21), 2.97-3.08 (m, 2H), 3.32 (s, 3H), 3.47 (bs, 2H), 4.00 (t,2H), 4.18 (q, 2H), 6.95 (d, 2H), 709-7.18 (m, 2H), 7.34 (d, 2H), 7.68(d, 2H).

Part B. Preparation of:

The impure ester of Part A (8.06 g, 14.2 mmol theoretical) washydrolyzed in 15 mL of ethanol, 15 mL of 1,4-dioxane and 9.5 mL of 6 NNaOH at 60° C. The solution was poured into water and extracted withether to remove color. Acidification with 1N HCl caused precipitation ofthe acid which was collected by filtration and washed with water andhexane then dried under high vacuum yielding the acid as an off whitesolid (5.90 g, 76.8% yield). NMR (CD₃OD w/K₂CO₃) δ 2.00 (q, 2H),2.07-2.19 (m, 4H), 2.32 (d, 2H), 2.48 (t, 2H), 2.79 (d, 2H1), 2.91 (d,2H), 3.45 (t, 2H), 4.06 (t, 2H), 7.04 (d, 2H), 7.20 (d, 2H), 7.29-7.35(m, 1H), 7.40 (s, 1H), 7.78 (d, 2H).

Part C. Preparation of:

To the acid of Part B (5.90, 10.9 mmol), EDC (2.9 g, 15.3 mmol), andHOBt (2.5 g, 16.4 mmol) in anhydrous NMP (33 mL) was added triethylamine(4.5 mL, 32.7 mmol). After heating at 60° C. for 1 hr, THP-hydroxylamine(1.9 g, 16.4 mmol) was added. The solution was stirred for 18 hr at 60°C., additional EDC (2.9 g, 15.3 mmol), HOBt (2.5 g, 16.4 mmol),triethylamine (4.5 mL, 32.7 mmol) and THP-hydroxylamine (1.9 g, 16.4mmol) were added. After 2 hr, the reaction was diluted with water (300mL) and extracted with ethyl acetate (3×150 mL). The combined organicswere washed with brine and dried over magnesium sulfate. Silica gelChromatography (ethyl acetate/hexanes) provided the protectedhydroxamate as a viscous impure colorless oil (5.70 g). ESMS m/z=641(M+H)⁺.

Part D. Preparation of:

In a vial were combined the aryl bromide from Part C (0.50 g, 0.78 mmol)in 3 mL of dimethoxyethyl ether, 4-chlorobenzeneboronic acid (185 mg,1.17 mmol), palladium tetrakistriphenylphosphine (45 mg, 0.04 mmol) and2M cesium carbonate (1.17 mL, 2.34 mmol). Mixture stirred vigorously at80° C. for 18 hr. Reaction poured onto 2 mL Chem-Elut tube prewettedwith 3 mL of water and eluted with ethyl acetate and methylene chloride.Purification by reverse phase chromatography (acetonitrile/water/0.05%TFA) gave the TFA salt of the deprotected material (239.6 mg) which wascarried on as is.

Part E. Preparation of:

The product from Part D (239.6 mg) was taken up in 4M hydrochloric acidin 1,4-dioxane (2 mL) and methanol (1-2 mL) and stirred for 0.5 hr thenconcentrated. This was repeated. Product crashed out of solution, wascollected by filtration, washed with diethyl ether and dried under highvacuum yielding the title compound as colorless solid (170.5 mg, 35%over two steps). ESMS m/z=587 (M+H)⁺. HRMS calcd. for C₃₀H₃₆ClN₂O₆S:587.1977 (M+H)⁺. Found: 587.1979.

Example 51 Preparation of1cyclopropyl-N-hydroxy-4-{[4-(3-{3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}propoxy)phenyl]sulfonyl}piperidine-4-carboxamidehydrochloride

Part A. In dry equipment under nitrogen, potassium trimethylsilonate(35.9 g, 0.28 mol) was dissolved in dimethylsulfoxide (250 mL) andgamma-butyrolactone (16.14 mL, 0.21 mol) was added over 10 min while thereaction temperature rose to 38° C. After stirring at ambienttemperature for 40 min, sodium hydride (8.4 g of a 60% oil dispersion,0.21 mol) was added portion wise over 20 min and the reactiontemperature rose to 43° C. Gas evolution was also observed. Afterstirring at ambient temperature for 50 min, a solution of ethyl1-cyclopropyl-4-[(4-fluorophenyl)sulfonyl]-4-piperidinecarboxylate (49.7g, 0.14 mol) in dimethylsulfoxide (50 mL) was added over 10 min as thereaction temperature rose to 38° C. The reaction was stirred at ambienttemperature for 30 min. The slurry was slowly poured into ice water (1.5L) and then extracted with hexanes (150 mL) 3 times followed by adiethyl ether extraction (300 mL). The aqueous layer was chilled to 5°C. and the pH adjusted to 6 with concentrated hydrochloric acid. Theslurry was filtered and the cake washed with 500 mL water two times. Thesolid was dried in vacuo to give the butyric acid as a white solid (47.5g, 77%). LCMS m/z=440 [M+H]⁺.

Part B. In dry equipment under nitrogen, the butyric acid from Part A(3.07 g, 7.0 mmol) was dissolved in dry dimethylacetamide (15 mL) andthe remaining reagents were added to the solution in the followingorder: N-hydroxybenzotriazole hydrate (1.42 g, 10.5 mmol), triethylamine(1.95 mL, 14.0 mmol), 4-(trifluoromethoxy)benzamidoxime (2.31 g, 10.5mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(2.68 g, 14.0 mmol). Additional dry dimethylacetamide (5 mL) was added.After 24 hr at 70° C., the reaction was concentrated in vacuo. Theresidue was taken up in ethyl acetate, washed with water, saturatedNaHCO₃, saturated sodium chloride solution, dried over Na₂SO₄, filtered,and concentrated in vacuo. Chromatography (on silica, ethylacetate/methanol/hexanes) provided the oxadiazole as a light white solid(3.38 g, 78%). LCMS m/z=624[M+H]⁺.

Part C. A slurry of the oxadiazole from Part B (3.36 g, 5.39 mmol), 2.5Nsodium hydroxide (6.5 mL, 16.2 mmol) and sodium hydroxide (0.86 g, 21.6mmol) in isopropanol (27 mL) was stirred at 75° C. for 5 hr. The heatwas removed and the reaction diluted with water (50 mL) and chilled to5° C. The pH was adjusted to 7 with concentrated hydrochloric acid. Thesolids were filtered, washed with hexanes, and dried in vacuo to givethe carboxylic acid as a white solid (3.1 g, 97%). LCMS m/z=596 [M+H]⁺.

Part D. In dry equipment under nitrogen, the carboxylic acid from Part C(2.9 g, 4.87 mmol) was dissolved in dry dimethylacetamide (10 mL) andthe remaining reagents were added to the solution in the followingorder: N-hydroxybenzotriazole hydrate (0.99 g, 7.3 mmol), triethylamine(2.03 mL, 14.6 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.86 g,7.31 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.87 g, 9.75 mmol). Additional dry dimethylacetamide (5mL) was added. After 29 hr at 40° C., the reaction was concentrated invacuo. The residue was taken up in ethyl acetate, washed with water,saturated NaHCO₃, saturated sodium chloride solution, dried over Na₂SO₄,filtered, and concentrated in vacuo. Chromatography (on silica, ethylacetate/methanol/hexanes) provided the THP hydroxamate as a white foam(1.48 g, 44%). LCMS m/z=695 [M+H]⁺.

Part E. To the THP hydroxamate from Part D (1.4 g, 2.02 mmol) was added4N HCl dioxane solution (5 mL, 20.2 mmol) and methanol (0.5 mL). Theslurry became very thick. Diethyl ether (50 mL) was added to and after 1hr at ambient temperature the reaction was filtered under nitrogen. Thesolids were washed with diethyl ether (150 mL) under nitrogen and driedin vacuo over phosphorus pentoxide to give the title compound as a whitesolid (1.4 g, 100%). HRMS (ES+) M+H⁺ calculated for C₂₇H₂₉N₄O₇S₁F₃611.1787, found 611.1773.

Example 52 Preparation of

Part A. In a vial were combined the aryl bromide from Part C of Example50 (0.50 g, 0.78 mmol) in 3 mL of dimethoxyethyl ether,3,4-difluorobenzeneboronic acid (185 mg, 1.17 mmol), palladiumtetrakistriphenylphosphine (˜45 mg, 0.04 mmol) and 2M cesium carbonate(1.17 mL, 2.34 mmol). Mixture stirred vigorously at 80° C. for 18 hr.Reaction poured onto 2 mL Chem-Elut tube prewetted with 3 mL of waterand eluted with ethyl acetate and methylene chloride. Purification byreverse phase chromatography (acetonitrile/water/0.05% TFA) gave the TFAsalt of the deprotected material (354.8 mg) which was carried on as is.

Part B. The product from Part D (354.8 mg) was taken up in 4Mhydrochloric acid in 1,4-dioxane (2 mL) and methanol (1-2 mL) andstirred for 30 min and then concentrated. This was repeated. Productcrashed out of solution, was collected by filtration, washed withdiethyl ether and dried under high vacuum yielding the title compound asa colorless solid (298.0 mg, 61% over two steps). ESMS m/z=589 (M+H)⁺.HRMS calcd. for C₃₀H₃₅F₂N₂O₆S: 589.2178 (M+H)⁺. Found: 589.2192.

Example 53 Preparation of

Part A. Preparation of:

A mixture of lithium chloride (1.71 g, 40.3 mmol),trifluoromethoxy-benzonitrile(5.00 g, 26.7 mmol), and sodium azide(1.75g, 26.7 mmol) in 2-methoxyethanol(26 mL) under an N₂ atmosphere wasrefluxed for 4 hr. The ambient mixture was poured into a mixture of ice(84 g) and concentrated hydrochloric acid (8.4 mL), and then stirreduntil the ice melted. The resulting white solid was collected byfiltration, washed with water, and dried for 2 hr in a 40° C. vacuumoven to provide the tetrazole in the form of an off white solid (4.86 g,79% yield). MS MH⁺ calcd. for C₈H₆N₄OF₃231, found 231.

Part B. Preparation of:

A solution of the tetrazole of Part A (2.00 g, 8.69 mmol) in NMP (12 mL)was added dropwise to an ambient mixture of 95% sodium hydride (0.438 g,18.2 mmol) in NMP (12 mL) under an N₂ atmosphere. After an 1 hr ofstirring, 2-(3-chloropropoxy)tetrahydro-2H-pyran(1.58 mL, 9.56 mmol) wasadded dropwise. The mixture was stirred at ambient temperature for 18 hrand then at 70° C. for 2 hr. The mixture was diluted with a solution ofwater (200 mL) and saturated NaHCO₃ (100 mL), and extracted with ethylacetate (3×10 mL). The organic layer was washed with water (2×10 mL) andbrine(100 mL), dried over MgSO₄, and concentrated in vacuo to give ayellow liquid. Flash chromatography purification (ethylacetate-hexane/silica gel) provided the pyran in the form of a whitesolid (1.46 g, 45% yield). Anal. Calcd. for C₁₆H₁₉N₄O₃F₃: C, 56.34; H,5.98; N, 7.73; S, 4.42. Found C, 56.13; H, 6.08; N, 7.65; S, 4.75.

Part C. Preparation of:

To an ambient solution of the pyran of Part B (1.40 g, 3.76 mmol) inMeOH (13.5 mL) was added a solution of acetyl chloride (0.896 mL, 13.1mmol) in MeOH (13.5 mL). After 15 min, the solution was concentrated invacuo to provide the alcohol in the form of a solid (1.02 g, 94% yield).MS MH⁺ calcd. for C₁₁H₁₂N₄O₂F₃ 289, found 289.

Part D. Preparation of:

To an ambient mixture of 95% sodium hydride (0.923 g, 38.5 mmol) in NMP(16 mL) under an N₂ atmosphere was added dropwise a solution of thealcohol of Part C (8.00 g, 27.7 mmol) in NMP(16 mL), and the mixture wasstirred at ambient temperature for 35 minutes. A solution of 1-benzyl4-tert-butyl 4-[(4-fluorophenyl)sulfonyl]piperidine-1,4-dicarboxylate(12.5 g, 26.3 mmol) in NMP (16 mL) was added dropwise to the reactionmixture. After 3 hr at 55° C., the ambient mixture was diluted withwater (700 mL) and extracted with ethyl acetate (3×150 mL). The organiclayer was washed with water (2×100 mL) and brine (100 mL), dried overMgSO₄, and concentrated in vacuo to produce a yellow oil (18.6 g).Chromatography purification (hexane-EA/silica gel) provided the sulfoneas a yellow oil (10.1 g, 52% yield). MS MH⁺ calcd. for C₃₅H₃₉N₅O₈SF₃746, found 746. Anal. Calcd. for C₃₅H₃₈N₅O₈SF₃ C, 56.37; H, 5.14; N,9.39; S, 4.30. Found C, 56.22; H, 4.96; N, 9.22; S, 4.37.

Part E. Preparation of:

A mixture of the sulfone of Part D (10.0 g, 13.4 mmol) and 10% palladiumon carbon (1.43 g, 1.34 mmol) in methanol (50 mL) was placed under an H₂atmosphere with a balloon at ambient temperature for 20 hr. The mixturewas filtered through a bed of celite and concentrated in vacuo toprovide the piperidine in the form of a pale yellow oil (7.57 g, 92%).The proton NMR spectrum was consistent for the desired compound.

Part F. Preparation of:

A mixture of the piperidine of Part E (3.50 g, 5.72 mmol),(bromomethyl)cyclopropane (0.67 mL, 6.87 mmol), and potassium carbonate(2.38 g, 17.2 mmol) in DMF (15 mL) was stirred at ambient temperaturefor 20 hr under an N₂ atmosphere. The mixture was diluted with water(700 mL) and extracted with ethyl acetate (3×mL). The organic layer waswashed with water (2×75 mL) and brine (75 mL), dried over MgSO₄, andconcentrated in vacuo to produce a yellow oil. Flash chromatographypurification (hexane-EA/silica gel) provided the alkylpiperidine in theform of a colorless oil(2.08 g, 55% yield): MS MH⁺ calcd. forC₃₁H₃₉N₅O₆SF₃ 666, found 666. Anal. Calcd. for C₃₁H₃₈N₅O₆SF₃: C, 55.93;H, 5.75; N, 10.52; S, 4.82. Found C, 55.85; H, 5.91; N, 10.25; S, 4.99.

Part G. Preparation of:

A solution of the alkylpiperidine of Part F (2.00 g, 3.00 mmol) intrifluoroacetic acid (10 mL, 130 mmol) was stirred at ambienttemperature for 1.7 hr. The mixture was concentrated in vacuo,triturated twice with ether, and dried in a 40° C. vacuum to provide theacid as a white solid (2.21 g, 102%). MS MH⁺ calcd. for C₂₇H₃₁N₅O₆SF₃610, found 610.

Part H. Preparation of:

A mixture of the crude acid of Part G (2.10 g, 3.44 mmol),1-hydroybenzotriazole hydrate(0.820 g, 6.07 mmol), triethylamine(5.57mL, 39.9 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine(0.835 g, 7.13mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(1.37 g, 7.13 mmol) in DMF (35 mL) under an N₂ atmosphere was stirred atambient temperature for 20 hr. The mixture was diluted with water (700mL) and extracted with ethyl acetate (3×200 mL). The organic layer waswashed with water (2×100 mL) and brine (100 mL), dried over MgSO₄, andconcentrated in vacuo to produce a yellow foam. Chromatographypurification (MeOH—CH₂Cl₂/silica gel) produced the O-protectedhydroxamate in the form of a white foam (1.60 g, 66%). MS MH⁺ calcd. forC₃₂H₄₀N₆O₇F₃S 709, found 709.

Part I. Preparation of:

A solution of the O-protected hydroxamate of Part H (1.50 g, 2.12 mmol)and acetyl chloride(0.677 mL, 10.2 mmol) in methanol (23 mL) was stirredat ambient temperature for 1 hr. The solution was diluted with ether anda solid formed. The solid was isolated by filtration, washed with ether,and dried in a 40° C. vacuum oven to produce the title compound as awhite solid (1.55 g, 82% yield). Anal. Calcd. for C₂₇H₃₁N₆O₆F₃S.HCl: C,49.05; H, 4.88; N, 12.71; Cl, 5.36; S, 4.85. Found C, 48.94; H, 4.72; N,12.71; Cl, 5.29; S, 4.94

Example 54 Preparation of

Part A. Preparation of:

To a solution of tert-butyl4-[(4-fluorophenyl)sulfonyl]tetrahydro-2H-pyran-4-carboxylate (5.0 g,14.6 mmol) and cesium carbonate (14.3 g, 43.8 mmol) in anhydrous DMSO(30 mL) was added ethylene glycol (8.1 mL, 146 mmol). The resultingreaction mixture was stirred at 80° C. for 3 hr. After cooling to roomtemperature, the mixture was poured into water (350 mL) and extractedwith ethyl acetate (3×). The organics were washed with brine and driedover magnesium sulfate. Silica gel chromatography (ethylacetate/methylene chloride) provided the alcohol as a colorless solid(2.33 g, 41%). NMR(CDCl₃) δ 1.45 (s, 9H), 2.13-2.20 (m, 4H), 3.22-3.33(m, 2H), 3.94-4.03 (m, 4H), 4.16 (q, 2H), 7.02 (d, 2H), 7.73 (d, 2H).ESMS m/z=404 (M+NH4)⁺. HRMS calcd. for C₁₈H₂₆O₇S NH₄: 404.1743 (M+N₄)⁺.Found: 404.1734.

Part B. Preparation of:

To a solution of the alcohol from Part A (0.50 g, 1.3 mmol) in CH₂Cl₂(2.5 mL) was added triethylamine (0.24 mL g, 1.7 mmol), followed bymesyl chloride. The resulting mixture was stirred at room temperaturefor 1.5 hr. The mixture was diluted with methylene chloride and washedwith 10% citric acid, washed with 5% sodium bicarbonate, washed withbrine, and dried over MgSO₄. Concentration produced the desired compoundin the form of a tan solid (0.62 g, 100%). NMR(CDCl₃) 1.45 (s, 9H),2.13-2.22 (m, 4H), 3.07 (s, 3H), 3.22-3.37 (m, 2H), 4.00 (dt, 2H),4.32-4.37 (m, 2H), 4.58-4.62 (m, 2H), 7.02 (d, 2H), 7.75 (d, 2H). ESMSm/z=482 (M+NH4)⁺.

Part C. Preparation of:

To a solution of 60% sodium hydride (39 mg, 0.98 mmol) in anhydrousdimethylformamide (2.5 mL) was added 3-cyanophenol (108 mg, 0.91 mmol).After stirring for 15 min, solution was clear. The mesylate from Part B(0.30 g, 0.65 mmol) in anhydrous dimethylformamide (1 mL) was added.After completion of the addition, the mixture as stirred at ambienttemperature overnight. The next morning, the mixture was poured onto a10 mL Chem-Elut tube, prewetted with 5 mL of water, and eluted withethyl acetate and CH₂Cl₂. Chromatography (silica gel with ethylacetate/hexane) produced the desired ester (0.27 g, 85%). NMR (CDCl₃)δ1.46 (s, 9H), 2.17-2.21 (m, 4H), 3.22-3.36 (m, 2H), 3.98 (dt, 2H),4.35-4.43 (m, 4H), 7.04 (d, 2H), 7.15-7.20 (m, 2H), 7.28 (dt, 1H), 7.39(t, 1H), 7.74 (d, 2H). ESMS m/z=505 (M+NH4)⁺. HRMS calcd. forC₂₅H₃₃N₂O₇S: 505.2008 (M+NH₄)⁺. Found: 505.2019.

Part D. Preparation of:

The ester of Part C (0.24 g, 0.49 mmol) was hydrolyzed in 5 mL ofmethylene chloride and 5 mL of trifluoroacetic acid. Concentration anddrying under high vacuum produced the desired acid (0.21 g, 100%). NMR(CD₃OD w/K₂CO₃) δ 2.01-2.11 (m, 2H), 2.20 (d, 2H), 3.32-3.42 (m, 2H),3.95 (dt, 2H), 4.38-4.45 (m, 4H), 7.13 (d, 2H), 7.26-7.34 (m, 3H), 7.45(t, 1H), 7.76 (d, 2H). ESMS m/z=449 (M+NH4)⁺. HRMS calcd. for C₂₁H₂₁NO₇SNH₄: 449.1382 (M+NH₄)⁺. Found: 449.1407.

Part E. Preparation of:

To a slurry of the acid of Part D (0.20 g, 0.46 mmol), HOBt (76 mg, 0.55mmol), and EDC (130 mg, 0.68 mmol) was added triethylamine (1.4 mmol)and THP-hydroxylamine (167 mg, 1.4 mmol) in a flask under N₂ in 2 mLanhydrous DMF. The resulting mixture was stirred at 40° C. overnight.The next morning, the mixture was poured onto 10 mL Chem-Elut tubeprewetted with 6 mL of water and eluted with ethyl acetate and CH₂Cl₂.Chromatography (silica gel, ethyl acetate/hexane) produced the productas a colorless oil (0.18 g, 74%).

Part F. Preparation of:

To the product from Part E (0.18 g, 0.34 mmol) in methanol (1-2 mL) wasadded 4M HCl in 1,4-dioxane (2.5 mL). The resulting mixture was stirredovernight. Reverse phase chromatography (water/acetonitrile/0.05% TFA)produced the desired compound as a colorless crystalline solid (25.0 mg16%). NMR(DMSO) δ 1.82-1.98 (m, 2H) 2.15-2.30 (m, 2H), 3.15, (t, 2H),3.86 (d, 2H), 4.44 (d, 4H), 7.10-7.25 (m, 3H), 7.38 (t, 1H), 7.44-7.52(m, 2H), 7.68 (d, 2H). ESMS m/z=465 (M+H)⁺. HRMS calcd. for C₂₁H₂₅N₂O₈S:465.1332 (M+H)⁺. Found: 465.1354.

Examples 55-89 In Vitro MMP Inhibition Analysis

Several hydroxamic acids and salts thereof were analyzed in in vitroassays to determine their ability to inhibit the MMP cleavage of peptidesubstrates. Inhibition (K_(i)) and IC₅₀ constants were calculated fromthe assayed hydroxamic acid-MMP interactions.

Human recombinant MMP-1, MMP-2, MMP-9, MMP-13, and MMP-14 were used inthis assay. All enzymes were prepared in Assignee's laboratoriesfollowing usual laboratory procedures. Protocols for the preparation anduse of these enzymes are available in the scientific literature. See,e.g., Enzyme Nomenclature (Academic Press, San Diego, Calif., 1992) (andthe citations therein). See also, Freije, et al., J Biol. Chem.,269(24), 16766-16773 (1994).

The MMP-1 proenzyme was purified from the spent media ofMMP-1-transfected HT-1080 cells provided by Dr. Harold Welgus ofWashington University (St. Louis, Mo.). The protein was purified on azinc chelating column.

The MMP-2 proenzyme was purified by gelatin Sepharose chromatographyfrom MMP-2-transfected p2AHT2 cells provided by Dr. Gregory Goldberg ofWashington University (St. Louis, Mo.).

The MMP-9 proenzyme was purified by gelatin Sepharose chromatographyfrom spent media of MMP-9-transfected HT1080 cells provided by Dr.Howard Welgus of Washington University (St. Louis, Mo.).

The MMP-13 was obtained as a proenzyme from a full-length cDNA cloneusing baculovirus, as described by V. A. Luckow, “Insect Cell ExpressionTechnology,” Protein Engineering: Principles and Practice, pp. 183-218(edited by J. L. Cleland et al., Wiley-Liss, Inc., 1996). The expressedproenzyme was first purified over a heparin agarose column, and thenover a chelating zinc chloride column. The proenzyme was then activatedby APMA for use in the assay. Further details on baculovirus expressionsystems may be found in, for example, Luckow et al., J. Virol., 67(8),4566-79 (1993). See also, O'Reilly et al, Baculovirus ExpressionVectors: A Laboratory Manual (W. H. Freeman and Co., New York, N.Y.,1992). See also, King et al., The Baculovirus Expression System: ALaboratory Guide (Chapman & Hall, London, England, 1992).

The MMP-14 full length cDNA was provided by Dr. Gregory Goldberg ofWashington University (St. Louis, Mo.). The catalytic domain enzyme wasexpressed in E. coli inclusion bodies, solubilized in urea, purified ona preparative C-14 reverse phase HPLC column, and then refolded in thepresence of zinc acetate and purified for use.

All MMPs were activated using 4-aminophenylmercuric acetate (“APMA”,Sigma Chemical, St. Louis, Mo.) or trypsin. MMP-9 also was activatedusing human recombinant MMP-3 (purified in Assignee's laboratoryfollowing standard cloning and purification techniques).

Two fluorogenic, methoxycoumarin-containing polypeptide substrates wereused in the MMP inhibition assays:MCA-ProLeuGlyLeuDpaAlaArgNH₂  (I)MCA-ArgProLeuGlyLeuDpaAlaArgGluArgNH₂  (II)Here, “Dpa” is 3-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl group, and“MCA” is 7-methoxycoumarin-4-yl acetyl. Substrate (I) was purchased fromBaychem (Redwood City, Calif.), and substrate II was prepared Assignee'slaboratory. Substrate I was used in the IC₅₀ determination assays, whilesubstrate II was used in the K_(i) determination assays. In the absenceof MMP inhibitory activity, either substrate is cleaved at the Gly-Leupeptide bond. This cleavage separates the highly fluorogenic peptidefrom the 2,4-dinitrophenyl quencher, thus resulting in increase offluorescent intensity.

The stock solutions of the assayed hydroxamic acids (or salts thereof)were prepared in 1% dimethyl sulfoxide (DMSO). These stock solutionswere diluted in Buffer A (100 mM Tris-HCl, 100 mM NaCl, 10 mM CaCl₂,0.05% polyoxyethylene 23 lauryl ether, pH 7.5) to obtain solutions withdifferent hydroxamic acid concentrations, i.e., assay solutions withdifferent concentrations of the assayed MMP inhibitory compound. Theexperiment controls contained the same amount of Buffer A/DMSO as theassayed sample, but contained no hydroxamic acid (or salt thereof).

The assays from which the IC₅₀ determinations were made were performedas follows. The MMPs were activated with either trypsin or APMA(4-aminophenylmercuric acetate, Sigma Chemical, St. Louis, Mo.). Theassayed hydroxamic acid samples were incubated in Microfluor™ WhitePlates (Dynatech, Chantilly, Va.) and analyzed on a Perkin Elmer L550plate reader (Norwalk, Conn.). The excitation wavelength was 328 nm, andthe emission wavelength −415 nm. All samples (assayed hydroxamic acidsand controls) were incubated in separate plates at room temperature inthe presence of 4 μM of MMP substrate (I). As stated in the previousparagraph, samples containing varying concentrations of the same assayedhydroxamic acid were prepared. Inhibition was measured as a reduction influorescent intensity as a function of MMP inhibitor concentration.

The assays from which the K_(i) determinations were made were performedas follows. The assayed hydroxamic acid samples were incubated inseparate wells of untreated white polystyrene plates (Nunc NalgeneInternational, Rochester, N.Y.), and analyzed on a Tecan SpectraFlourPlus plate reader. The excitation wavelength was 330 nm, and theemission wavelength −420 nm. All samples (assayed hydroxamic acids andcontrols) were incubated in separate plate wells at room temperature for1 hr in the presence of 4 μM of MMP substrate (II). In the absence ofMMP inhibitory activity, substrate II was cleaved at the Gly-Leu bondresulting in an increase of relative fluorescence. Inhibition wasobserved as a reduced rate of this increase in relative fluorescence.The various hydroxamic acids were analyzed using a single low enzymeconcentration with a single substrate concentration fixed at or belowthe K_(m). This protocol is a modification of method by Knight et al.,FEBS Lett., 296(3), 263-266 (1992). Apparent inhibitory constants weredetermined by non-linear regression of reaction velocity as a functionof inhibitor and enzyme concentration using Morrison's equation, asdescribed by Kuzmic, Anal. Biochem. 286, 45-50 (2000). Modificationswere made in the non-linear regression method to allow a common controlreaction rate and effective enzyme concentration to be shared betweenall dose-response relationships on a given assay plate. Since thesubstrate concentration was chosen to be at or below the K_(m), theapparent K_(i)'s from this analysis were reported as K_(i)'s withoutcorrection for the influence of substrate.

The above protocols were used to determine IC50 constants and K_(i)values values for several of the compounds in Examples 1-52 above. Theresults are shown in Table 5. All values in Table 5 are given in nMunits. The K_(i) measurements are in parenthesis.

TABLE 5 MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Ex. # Compound IC₅₀ (Ki) IC₅₀(Ki) IC₅₀ (Ki) IC₅₀ (Ki) IC₅₀ (Ki) 55 Example 17 550 1.6 56 Example18 >10000 537 6000 1.8 >10000 57 Example 19 >10000 9000 5190 15 >1000058 Example 20 >10000 1.8 498 1.8 >10000 59 Example 21 >10000 450 >100003.5 >10000 60 Example 22 >10000 1000 >10000 4.9 >10000 61 Example25 >10000 247.2 8498 1.8 >10000 62 Example 26 >10000 52.0 44293.4 >10000 63 Example 27 >10000 83.9 9366 0.2 >10000 64 Example28 >10000 76.4 3710 7.0 >10000 65 Example 30 >10000 22.6 809 1.3 >1000066 Example 31 >10000 346.3 5651 2.1 >10000 (>10000) (412.93) (1596.8)(1.503) (>10000) 67 Example 32 >10000 217.7 4076 0.8 >10000 68 Example33 >10000 16 7.9 1  4936 69 Example 34   429 36.6 >10000 3.0 >10000 70Example 35 >10000 600 >10000 3 >10000 71 Example 36 95 2.4 72 Example 37 8708 30.3 449 1.4 >10000 73 Example 38 >10000 157.5 1026.3 0.9 >10000(>10000) (369.98) (6.55) (4451.2)  74 Example 39 (>10000) 1299   (2360)0.9 (>10000)   (1640) (3.04) 75 Example 40 >10000 112.4 413 0.5 >10000(>10000) (215.98) (585.44) 0.58) (>10000) 76 Example 41 >10000 357.51597 2.0 >10000 (>10000) (414.99) (1465.7) (1.056) (>10000) 77 Example42 >10000 100.3 382.5 0.3 >10000 (>10000) (186.28)  (661.7) (0.486)(>10000) 78 Example 43 >10000 4.8 1.0 1.0  2084 79 Example 44 >10000133.2 154.5 1.4  4976 80 Example 45 (>10000) (224.78) (499.18) (0.62)(>10000) 81 Example 46 >10000 320.9 1966 3.1 >10000 (>10000) (786.36)(417.51) (2.29) (>10000) 82 Example 47 (>10000) 18.2 (118.75) 0.2(3317.66)  (19.15) (308.77) (0.304)  (5293)  (46.49) (0.423) 83 Example48 >10000 104.6 4450.3 0.2 >10000 (>10000) (227.54)  (159.2) (0.127)(>10000) 84 Example 49 >10000 273.9 4056 0.3 >10000 (>10000) (439.76)(1947.90)  (0.439) (>10000) 85 Example 50 (>10000) (1127.89)  (304.41)(0.60) (>10000) 86 Example 51 >10000 251.6 7983 0.2 >10000 (5160.20) (93.68)  (98.72) (1.697)  (687.93) 87 Example 52 (>10000) (542.89)(617.14) (0.81) (>10000) 88 Example 53 >10000 383.5 75.5 1.0 >10000(>10000)   (697)   (2900) (0.662) (>10000) 89 Example 54 (>10000) 35.5  (388) 10.5  (4120) (64.8)

Example 90 In Vivo Angiogenesis Assay

The study of angiogenesis depends on a reliable and reproducible modelfor the stimulation and inhibition of a neovascular response. Thecorneal micropocket assay provides such a model of angiogenesis in thecornea of a mouse. See, “A Model of Angiogenesis in the Mouse Cornea”,Investigative Ophthalmology & Visual Science, Vol. 37, No. 8, pp.1625-1632 (July 1996).

In this assay, uniformLy sized Hydron™ pellets containing bFGF andsucralfate are prepared and surgically implanted into the stroma mousecornea adjacent to the temporal limbus. The pellets are formed by makinga suspension of 20 μL sterile saline containing 10 μg recombinant bFGF,10 mg of sucralfate and 10 μL of 12 percent Hydron™ in ethanol. Theslurry is then deposited on a 10×10 mm piece of sterile nylon mesh.After drying, the nylon fibers of the mesh are separated to release thepellets.

The corneal pocket is made by anesthetizing a 7 week old C₅₇B1/6 femalemouse, then proptosing the eye with a jeweler's forceps. Using adissecting microscope, a central, intrastromal linear keratotomy ofapproximately 0.6 mm in length is performed with a #15 surgical blade,parallel to the insertion of the lateral rectus muscle. Using a modifiedcataract knife, a lamellar micropocket is dissected toward the temporallimbus. The pocket is extended to within 1.0 mm of the temporal limbus.A single pellet is placed on the corneal surface at the base of thepocket with a jeweler's forceps. The pellet is then advanced to thetemporal end of the pocket. Antibiotic ointment is then applied to theeye.

Mice are dosed on a daily basis for the duration of the assay. Dosing ofthe animals is based on bioavailability and overall potency of thecompound. An exemplary dose is 10 or 50 mg/kg (mpk) bid, po.Neovascularization of the corneal stroma is permitted to continue underthe influence of the assayed compound for 2 days. At that point, thedegree of angiogenic inhibition is scored by viewing the neovascularprogression with a slit lamp microscope.

The mice are anesthetized and the studied eye is once again proptosed.The maximum vessel length of neovascularization, extending from thelimbal vascular plexus toward the pellet is measured. In addition, thecontiguous circumferential zone of neovascularization is measured asclock hours, where 30 degrees of arc equals one clock hour. The area ofangiogenesis is calculated as follows.${area} = \frac{\left( {0.4 \times {clock}\quad{hours} \times 3.14 \times {vessel}\quad{length}\quad\left( {{in}\quad{mm}} \right)} \right)}{2}$

Five to six mice should be utilized for each compound in each study. Thestudied mice are thereafter compared to control mice and the differencein the area of neovascularization is recorded as an averaged value. Eachgroup of mice so studied constitutes an “n” value of one, so that “n”values greater than one represent multiple studies whose averaged resultis provided in the table. A contemplated compound typically exhibitsabout 25 to about 75 percent inhibition, whereas the vehicle controlexhibits zero percent inhibition.

Example 91 Tumor Necrosis Factor Assays

Cell Culture.

The cells used in the assay are the human moncytic line U-937 (ATCCCRL-1593). The cells are grown in RPMI w/10% FCS and PSG supplement(R-10) and are not permitted to overgrow. The assay is carried out asfollows:

1. Count, then harvest cells by centrifugation. Resuspend the pellet inR-10 supplement to a concentration of 1.540×10⁶ cells/mL.

2. Add test compound in 65 uL R-10 to the appropriate wells of a 96-wellflat bottom tissue culture plate. The initial dilution from a DMSO stock(100 mM compound) provides a 400 uM solution, from which five additionalthree-fold serial dilutions are made. Each dilution of 65 ul (intriplicate) yields final compound test concentrations of 100 μM, 33.3μM, 11.1 μM, 3.7 μM, 1.2 μM and 0.4 μM.

3. The counted, washed and resuspended cells (200,000 cells/well) in 130μL are added to the wells.

4. Incubation is for 45 min to 1 hr at 37° C. in 5% CO₂ in a watersaturated container.

5. R-10 (65 uL)containing 160 ng/mL PMA (Sigma) is added to each well.

6. The test system is incubated at 37° C. in 5% CO2 overnight (18-20 hr)under 100% humidity.

7. Supernatant, 150 μL, is carefully removed from each well for use inthe ELISA assay.

8. For toxicity, a 50 μL aliquot of working solution containing 5 mLR-10, 5 mL MTS solution [CellTiter 96 AQueous One Solution CellProliferation Assay Cat.#G358/0,1 (Promega Biotech)] and 250 ul PMSsolution are added to each well containing the remaining supernatant andcells and the cells incubated at 37° C. in 5% CO₂ until the colordevelops. The system is excited at 570 nm and read at 630 nm.

TNF Receptor II ELISA Assay

1. Plate 100 μL/well 2 ug/mL mouse anti-human TNFrII antibody (R&DSystems #MAB226) in 1×PBS (pH 7.1, Gibco) on NUNC-Immuno Maxisorb plate.Incubate the plate at 4° C. overnight (about 18-20 hr).

2. Wash the plate with PBS-Tween (1×PBS w/0.05% Tween).

3. Add 200 μL 5% BSA in PBS and block at 37° C. in a water saturatedatmosphere for 2 hr.

4. Wash the plate with PBS-Tween.

5. Add sample and controls (100 ul of each) to each well. The standardsare 0, 50, 100, 200, 300 and 500 pg recombinant human TNFrII (R&DSystems #226-B2) in 100 μL 0.5% BSA in PBS. The assay is linear tobetween 400-500 pg of standard.

6. Incubate at 37° C. in a saturated atmosphere for 1.5 hr.

7. Wash the plate with PBS-Tween.

8. Add 100 μL goat anti-human TNFrII polyclonal (1.5 μg/mL R&D Systems#AB226-PB in 0.5% BSA in PBS).

9. Incubate at 37° C. in a saturated atmosphere for 1 hr.

10. Wash the plate with PBS-Tween.

11. Add 100 μl anti-goat IgG-peroxidase (1:50,000 in 0.5% BSA in PBS,Sigma #A5420).

12. Incubate at 37° C. in a saturated atmosphere for 1 hr.

13. Wash the plate with PBS-Tween.

14. Add 10 μL KPL TMB developer, develop at room temperature (usuallyabout 10 min), then terminate with phosphoric acid and excite at 450 nmand read at 570 nm.

TNFα ELISA Assay.

Coat Immulon® 2 plates with 0.1 mL/well of 1 ug/mL Genzyme mAb in 0.1 MNaHCO3 pH 8.0 buffer overnight (about 18-20 hr) at 4° C., wrappedtightly in Saran® wrap.

Flick out coating solution and block plates with 0.3 mL/well blockingbuffer overnight at 4° C., wrapped in Saran® wrap.

Wash wells thoroughly 4× with wash buffer and completely remove all washbuffer. Add 0.1 mL/well of either samples or rhTNFα standards. Dilutesamples if necessary in appropriate diluant (e.g. tissue culturemedium). Dilute standard in same diluant. Standards and samples shouldbe in triplicates.

Incubate at 37° C. for 1 hr in humified container.

Wash plates as above. Add 0.1 mL/well of 1:200 dilution of Genzymerabbit anti-hTNFa.

Repeat incubation.

Repeat wash. Add 0.1 mL/well of 1 μg/mL Jackson goat anti-rabbit IgG(H+L)-peroxidase.

Incubate at 37° C. for 30 min.

Repeat wash. Add 0.1 mL/well of peroxide-ABTS solution.

Incubate at room temperature for 5-20 min.

Read OD at 405 nm.

12 Reagents are:

-   -   Genzyme mouse anti-human TNF monoclonal (Cat.# 80-3399-01)    -   Genzyme rabbit anti-human TNF polyclonal (Cat.#IP-300)    -   Genzyme recombinant human TNF (Cat.#TNF-H).    -   Jackson Immunoresearch peroxide-conjugated goat anti-rabbit IgG        (H+L) (Cat.#111-035-144).    -   Kirkegaard/Perry peroxide ABTS solution (Cat#50-66-01).    -   Immulon 2 96-well microtiter plates.    -   Blocking solution is 1 mg/mL gelatin in PBS with 1× thimerasol.    -   Wash buffer is 0.5 mL Tween® 20 in 1 liter ofPBS.

Example 92 In Vitro Aggrecanase Inhibition Analysis

Assays for measuring the potency (IC₅₀) of a compound toward inhibitingaggrecanase are known in the art.

One such assay, for example, is reported in European Patent ApplicationPubl. No. EP 1 081 137 A1. In that assay, primary porcine chondrocytesfrom articular joint cartilage are isolated by sequential trypsin andcollagenase digestion followed by collagenase digestion overnight andare plated at 2×10⁵ cells per well into 48 well plates with 5 μCi/ml³⁵S(1000 Ci/mmol) sulphur in type 1 collagen coated plates. Cells areallowed to incorporate label into their proteoglycan matrix(approximately 1 week) at 37° C. under an atmosphere of 5% CO₂. Thenight before initiating the assay, chondrocyte monolayers are washed 2times in DMEM/1% PSF/G and then allowed to incubate in fresh DMEM/1% FBSovernight. The next morning, chondrocytes are washed once in DMEM/1%PSF/G. The final wash is allowed to sit on the plates in the incubatorwhile making dilutions. Media and dilutions are made as described in thefollowing Table 6:

TABLE 6 control media DMEM alone IL-1 media DMEM + IL-1 (5 ng/ml) drugdilutions Make all compound stocks at 10 mM in DMSO. Make a 100 μM stockof each compound in DMEM in 96-well plate. Store in freezer overnight.The next day, perform serial dilutions in DMEM with IL-1 to 5 μM, 500nM, and 50 nM. Aspirate final wash from wells and add 50 μM of com-pound from above dilutions to 450 μL of IL-1 media in appropriate wellsof the 48 well plates. Final compound concentrations equal 500 nM, 50nM, and 5 nM. All samples completed in triplicate with control and IL-1alone on each plate.Plates are labeled and only the interior 24 wells of the plate are used.On one of the plates, several columns are designated as IL-1 (no drug)and control (no IL-1, no drug). These control columns are periodicallycounted to monitor 35S-proteoglycan release. Control and IL-1 media areadded to wells (450 μL) followed by compound (50 μL) so as to initiatethe assay. Plates are incubated at 37° C. with 5% CO₂ atmosphere. At40-50% release (when CPM from IL-1 media is 4-5 times control media) asassessed by liquid scintillation counting (LSC) of media samples, theassay is terminated (about 9 to about 12 hours). Media is removed fromall wells and placed into scintillation tubes. Scintillate is added andradioactive counts are acquired (LSC). To solubilize cell layers, 500 μLof papain digestion buffer (0.2 M Tris, pH 7.0, 5 mM DTT, and 1 mg/mlpapain) is added to each well. Plates with digestion solution areincubated at 60° C. overnight. The cell layer is removed from the platesthe next day and placed in scintillation tubes. Scintillate is thenadded, and samples counted (LSC). The percent of released counts fromthe total present in each well is determined. Averages of thetriplicates are made with control background subtracted from each well.The percent of compound inhibition is based on IL-1 samples as 0%inhibition (100% of total counts).

Another assay for measuring aggrecanase inhibition is reported in WIPOInt'l Publ. No. WO 00/59874. That assay reportedly uses activeaggrecanase accumulated in media from stimulated bovine cartilage (BNC)or related cartilage sources and purified cartilage aggrecan monomer ora fragment thereof as a substrate. Aggrecanase is generated bystimulation of cartilage slices with interleukin-1 (IL-1), tumornecrosis factor alpha (TNF-α), or other stimuli. To accumulate BNCaggrecanase in culture media, cartilage reportedly is first depleted ofendogenous aggrecan by stimulation with 500 ng/ml human recombinant IL-βfor 6 days with media changes every 2 days. Cartilage is then stimulatedfor an additional 8 days without media change to allow accumulation ofsoluble, active aggrecanase in the culture media. To decrease theamounts of matrix metalloproteinases released into the media duringaggrecanase accumulation, agents which inhibit MMP-1, -2, -3, and -9biosynthesis arc included during stimulation. This BNC conditioned mediacontaining aggrecanase activity is then used as the source ofaggrecanase for the assay. Aggrecanase enzymatic activity is detected bymonitoring production of aggrecan fragments produced exclusively bycleavage at the Glu373-Ala374 bond within the aggrecan core protein byWestern analysis using the monoclonal antibody, BC-3 (Hughes, et al.,Biochem J, 305(3):799-804 (1995)). This antibody reportedly recognizesaggrecan fragments with the N-terminus, 374ARGSVIL, generated uponcleavage by aggrecanase. The BC-3 antibody reportedly recognizes thisneoepitope only when it is at the N-terminus and not when it is presentinternally within aggrecan fragments or within the aggrecan proteincore. Only products produced upon cleavage by aggrecanase reportedly aredetected. Kinetic studies using this assay reportedly yield a Km of1.5+/−0.35 μM for aggrecanase. To evaluate inhibition of aggrecanase,compounds are prepared as 10 mM stocks in DMSO, water, or other solventsand diluted to appropriate concentrations in water. Drug (50 μL) isadded to 50 μL of aggrecanase-containing media and 50 μL of 2 mg/mlaggrecan substrate and brought to a final volume of 200 μL in 0.2 MTris, pH 7.6, containing 0.4 M NaCl and 40 mM CaCl₂. The assay is runfor 4 hr at 37° C., quenched with 20 mM EDTA, and analyzed foraggrecanase-generated products. A sample containing enzyme and substratewithout drug is included as a positive control and enzyme incubated inthe absence of substrate serves as a measure of background. Removal ofthe glycosaminoglycan side chains from aggrecan reportedly is necessaryfor the BC-3 antibody to recognize the ARGSVIL epitope on the coreprotein. Therefore, for analysis of aggrecan fragments generated bycleavage at the Glu373-Ala374 site, proteoglycans and proteoglycanfragments are enzymatically deglycosylated with chondroitinase ABC (0.1units/10 μg GAG) for 2 hr at 37° C. and then with keratanase (0.1units/10 μg GAG) and keratanase II (0.002 units/10 μg GAG) for 2 hr at37° C. in buffer containing 50 mM sodium acetate, 0.1 M Tris/HCl, pH6.5. After digestion, aggrecan in the samples is precipitated with 5volumes of acetone and resuspended in 30 μL of Tris glycine SDS samplebuffer (Novex) containing 2.5% beta mercaptoethanol. Samples are loadedand then separated by SDS-PAGE under reducing conditions with 4-12%gradient gels, transferred to nitrocellulose and immunolocated with1:500 dilution of antibody BC3. Subsequently, membranes are incubatedwith a 1:5000 dilution of goat anti-mouse IgG alkaline phosphatasesecond antibody and aggrecan catabolites visualized by incubation withappropriate substrate for 10-30 minutes to achieve optimal colordevelopment. Blots are quantitated by scanning densitometry andinhibition of aggrecanase determined by comparing the amount of productproduced in the presence versus absence of compound.

Examples 93-645

Additional hydroxamic acid compounds (and salts thereof) can be preparedby one skilled in the art using methods similar to those described inExamples 1-54 alone or in combination with techniques well known in theart. Such compounds include, for example, the compounds summarized inthe following Table 7. Table 7 also summarizes in vitro MAD inhibitionresults obtained by Applicants with the listed hydroxamic acids. As withTable 5, all in vitro K_(i) and IC₅₀ results in Table 7 are given in nMunits. The Ki measurements are in parenthesis.

TABLE 7 Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Ex # StructureMass Mass IC₅₀ (Ki) IC₅₀ (Ki) IC₅₀ (Ki) IC₅₀ (Ki) IC₅₀ (Ki) 93

(>10000) 746.6 (676) (1120) 15.5 (9.29) (>10000) 94

17.8 3.7 95

>10000 (>10000) 91.4 (149) 1204.6 (788) 2.7 >10000 (5410) 96

39.1 15.3 97

486.1586 486.1602 (7360) 185.0 (295) (473) 3.3 (5.57) (>10000) 98

510.1950 510.1947 >10000 (>10000) 316.2 (625) 2418 (1450) 1.8(9.15) >10000 (>10000) 99

482.1637 482.1661 >10000 245.8 3435 0.4 >10000 100

1691.4 152.6 101

503.1480 503.1465 18.2 0.2 102

483.1260 483.1264 12.4 1.2 103

613 613 >10000 85.8 1134 0.4 >10000 104

44.2 0.8 105

>10000 1368.8 7694 9.7 >10000 106

>10000 1046.6 >10000 3.5 >10000 107

34.0 5.5 108

433.7 20.0 109

524.2107 524.2136 (>10000) 5410.3 (8100) (>10000) 152.1 (93.1) (>10000)110

518.1449 518.1505 (>10000) 1198.5 (1120) (4340) 7.6 (11.4) (>10000) 111

500.1543 500.1561 (>10000) 559.4 (769) (2680) 2.0 (6.39) (>10000) 112

566.1460 566.1500 (>10000) 66.4 (3970) (8850) 37.9 (51.2) (>10000) 113

483.1590 483.1597 >10000 (>10000) 20.3 (42.30) 1980.5 (161.22) 0.2(0.312) 7725 (3481.8) 114

516.1248 516.1259 (>10000) 1010.6 (1500) (4870) 5.2 (4.2) (>10000) 115

500.1543 500.1550 >10000 (>10000) 311.9 (807) >10000 (1980) 0.9(2.24) >10000 (>10000) 116

496.1794 496.1811 (>10000) 1053.2 (1250) (5550) 11.2 (5.1) (>10000) 117

510.1950 510.1965 (>10000) 1744.7 (3640) (9910) 16.0 (21) (>10000) 118

530.1404 530.1418 (>10000) 1862.0 (2650) (>10000) 29.8 (18.8) (>10000)119

526.1899 526.1920 (>10000) 1187.6 (1680) (3950) 18.3 (31.4) (>10000) 120

514.1700 514.1724 >10000 1171.6 >10000 5.8 >10000 121

550.0858 550.0846 (>10000) 2469.3 (4620) (>10000) 21.6 (26.9) (>10000)122

518.1449 518.1470 >10000 759.7 7668 1.9 >10000 123

500.1543 500.1545 >10000 (>10000) 383.0 (793) >10000 (2130) 1.4(7.35) >10000 (>10000) 124

550.0858 550.0896 (>10000) 2151.5 (5730) (>10000) 21.9 (20.1) (>10000)125

2937 (3584.24) 27.3 (51.34) 962.9 (146.43) 0.2 (0.17) 5825 (1666.65) 126

550.0858 550.0881 (>10000) 3260.4 (6360) (>10000) 349.0 (81.3) (>10000)127

496.1794 496.1800 >10000 (>10000) 1380.0 (2160) >10000 (4230) 5.5(16.2) >10000 (>10000) 128

615.2902 615.2852 (>10000) 658.7 (1130) (3550) 23.7 (13.8) (>10000) 129

(>10000) 41.4 (50) (110) 1.9 (0.27) (>10000) 130

4611 4.7 50.2 0.3 499.8 131

107.9 4.5 132

61.7 3.7 133

84.4 4.3 134

>10000 2382 >10000 7.7 >10000 135

637.1332 637.1315 (>10000) 24.3 (58.5) (457) 2.9 (0.761) (9510) 136

229.4 4.4 137

(>10000) 20.4 (36.6) (604) 7.0 (0.976) (>10000) 138

>10000 247.3 1896 2.1 >10000 139

553.2172 553.2176 >10000 (>10000) 207.7 (1410) 4514 (1390) 0.4(2.89) >10000 (>10000) 140

>10000 (>10000) 48.0 (708) 1692 (754) 0.5 (0.895) >10000 (>10000) 141

577 577 32.5 3.6 142

(>10000) 58.6 (96.4) (310) 7.5 (1.34) (>10000) 143

4.9 1.4 144

>10000 238.6 5989 2.5 >10000 145

>10000 816.9 9438 2.0 >10000 146

11.1 0.4 147

580.1617 580.1620 (>10000) 4746.8 (>10000) (7970) 28.3 (23.9) (>10000)148

(8790) 272.0 (213) (427) 3.1 (1.72) (5150) 149

(>10000) 77.1 (84.1) (94.5) 1.3 (1.18) (2530) 150

>10000 (>10000) 135.5 (159) 529.9 (125) 0.6 (0.587) 6630 (5510) 151

559 559 38.4 2.6 152

629.1893 629.1885 >10000 (>10000) 58.8 (149) 72.3 (44.5) 11.8(2.66) >10000 (>10000) 153

192.5 7.6 154

498.0586 498.0591 >10000 (>10000) 10.9 (33.9) 111 (151) 0.8 (0.95) 9123(3910) 155

573.2383 573.2413 >10000 (>10000) 13.8 (37.9) 1173.7 (172) 9.7(1.58) >10000 (9370) 156

32.1 1.0 157

>10000 (>10000) 182.1 (419) 2473 (1390) 3.5 (4.01) >10000 (>10000) 158

530.1404 530.1446 >10000 (>10000) 2184 (2730) 5630 (3950) 3.6(5.1) >10000 (>10000) 159

532.1605 532.1632 1368.6 24.4 160

538.2263 538.2275 >10000 (>10000) >10000 (>10000) (>10000) 505.1(>10000) 161

514.1700 514.1708 >10000 (>10000) 1001.1 (1760) 2625 (1730) 2.6(20.3) >10000 162

530.1404 530.1428 (>10000) 1596.6 (2370) (3150) 15.6 (12) (>10000) 163

514.1700 514.1680 >10000 (>10000) 1370.7 (1010) 2880 (2500) 2.5(11.6) >10000 (>10000) 164

510.1950 510.1940 (>10000) 1073.2 (978) (2720) 20.0 (6.85) (>10000) 165

524.2107 524.2112 (>10000) 3396.2 (>10000) (9750) 146.9 (144) (>10000)166

544.1561 644.1606 (>10000) 3081.7 (8090) (8690) 135.9 (63.4) (>10000)167

540.2056 540.2029 (>10000) 3739.4 (128) (68.1) 147.0 (78.9) (>10000) 168

528.1856 528.1863 (>10000) 3428.2 (5500) (6500) 34.3 (27.3) (>10000) 169

564.1014 564.1026 (>10000) 4363.5 (5360) (6500) 70.7 (20.4) (>10000) 170

532.1605 532.1618 (>10000) 1608.7 (1410) (1500) 3.3 (6.79) (>10000) 171

564.1014 564.1028 (>10000) 2288.8 (3190) (6600) 62.8 (12.5) (>10000) 172

564.1014 564.1032 (>10000) 5163.1 (>10000) (9440) 377.0 (71.1) (>10000)173

509.1950 509.1954 (>10000) 2120.4 (4090) (3480) 12.2 (11.5) (>10000) 174

>10000 708.6 4017 5.2 >10000 175

601.2696 601.2657 >10000 (>10000) 438.0 (872) 7296.6 (1390) 1.4(2.01) >10000 (>10000) 176

108.9 7.8 177

333.2 17.0 178

>10000 (>10000) 28.4 (39.3) 1166.4 (306) 7.8 (1.71) >10000 (>10000) 179

246.9 1.1 180

443.0 17.0 181

>10000 (1850) 13.9 (15.8) 26.4 (40.5) 0.3 (0.27) 8059 (4830) 182

>10000 (6540) 33.1 (34.3) 62.1 (85.4) 0.5 (0.212) >10000 (5850) 183

(>10000) 708.0 (643) (2510) 21.0 (15.1) (>10000) 184

1528.7 30.4 103.5 3.9 2715.4 185

(>10000) 84.7 (116) (220) 12.4 (3.73) (>10000) 186

609.9 13.5 187

3868 3.6 11.2 1.8 1425 188

>10000 4.7 48.2 0.3 3537.7 189

1070 19.3 24.1 1.9 4316 190

>10000 (>10000) 165.9 (283) 1742.6 (669) 0.5 (0.6) >10000 (>10000) 191

6956 341.2 383.4 9.5 >10000 192

1256.4 15.4 193

5931.6 312.3 272.5 6.8 >10000 194

>10000 221.6 515.7 6.2 >10000 195

4381.7 20.6 45.8 7.5 2741.5 196

32.2 11.4 197

>10000 (>10000) 13.2 (30.7) 432.2 (334) 0.5 (0.37) >10000 (>10000) 198

4527.4 834.9 199

(>10000) 133.2 (228) (59.5) 7.4 (3.09) (>10000) 200

7498 84.0 1207.2 0.6 >10000 201

538.2376 538.2362 >10000 127.7 4509.5 0.7 >10000 202

1604.4 41.9 203

>10000 4.2 6.0 1.0 >10000 204

>10000 145.7 1824.8 0.6 >10000 205

4780.2 17.6 206

>10000 92.6 59.4 15.8 3112 207

>10000 114.3 126.7 3.7 >10000 208

>10000 230.2 6587.6 0.6 >10000 209

>10000 172.5 905.6 1.4 >10000 210

>10000 6.9 284.6 1.3 >10000 211

9653 26.2 863.5 0.4 >10000 212

1408 4.1 212.2 0.3 >10000 213

>10000 54.8 2204 2.2 >10000 214

>10000 15.8 4239 3.3 >10000 215

>10000 20.3 767.9 0.3 >10000 216

1952.2 51.2 217

>10000 48.9 5179 4.6 >10000 218

>10000 40.4 2973 1.4 >10000 219

>10000 (5600) 60.8 (105) 77.7 (59.5) 0.4 (0.355) >10000 (7940) 220

>10000 409.7 1466.8 5.7 >10000 221

8796.4 243.8 222

138.1 13.3 223

69.7 11.9 224

>10000 193.5 1466.8 4.7 >10000 225

2332.3 17.8 226

>10000 222.0 2144.0 4.3 >10000 227

2.7 0.2 228

6871 (3940) 11.4 (22.4) 180.4 (247) 0.2 (0.324) >10000 (6290) 229

5033 (955) 12.2 (10.4) 293.7 (281) 1.7 (0.27) >10000 (7870) 230

>10000 555.2 1017.7 1.1 >10000 231

>10000 1.6 10.2 0.2 641.7 232

>10000 74.2 877.7 5.6 >10000 233

>10000 (>10000) 25.5 (60.18) 831.8 (509.42) 0.1 (0.137) >10000 (>10000)234

596.2430 596.2441 213.4 10.3 235

421.7 26.0 236

7.6 3.4 237

>10000 42.5 1111 0.7 >10000 238

>10000 78.7 1186.1 1.2 >10000 239

236.9 2.5 240

>10000 84.0 1428.4 0.7 >10000 241

>10000 60.2 944.2 1.3 >10000 242

2720.2 203.0 243

9313.6 49.4 2101.9 0.5 >10000 244

3250.6 18.8 108.2 0.7 >10000 245

>10000 8.6 61.1 0.2 >10000 246

1166.7 7.5 104.7 3.0 >10000 247

3610.8 445.1 341.1 1.1 >10000 248

>10000 15.7 105.6 0.2 1704.1 249

>10000 (>10000) 226 (333) 3628.6 (1490) 5.09 (1.49) >10000 (>10000) 250

4406.1 (1440) 2.5 (3.12) 22.5 (12.5) 0.3 (0.127) 7630.2 (1700) 251

182.4 5.4 252

5602.7 47.9 1052.4 0.2 >10000 253

1448.2 32.4 254

>10000 138.3 968.2 1.7 >10000 255

51.3 1.9 256

>10000 0.1 37.9 <0.1 >10000 257

>10000 173.8 6227 0.5 >10000 258

>10000 173.5 1956 1.7 >10000 259

7256 201.1 1876 0.7 >10000 260

1159 13.2 391.0 1.8 >10000 261

>10000 178.3 1185.0 1.9 >10000 262

>10000 118.3 1702.3 3.0 >10000 263

>10000 87.7 3267.5 3.8 >10000 264

>10000 162.8 287.1 5.3 >10000 265

40.0 0.2 266

>10000 391.2 202.6 9.1 >10000 267

>10000 18.5 106.7 >10000 268

>10000 125.9 674.0 2.5 >10000 269

>10000 897.9 2755 1.8 >10000 270

521.8 8.1 271

>10000 8.7 531.8 2.9 >10000 272

399 4.2 152.1 2.8 >10000 273

405.1332 405.1335 1010.7 304.0 274

402.1223 402.1225 9864 15.4 33.6 4.1 >10000 275

115.2 1.7 276

6670.4 17.4 196.3 2.8 7019.9 277

>10000 3.5 41.5 0.2 >10000 278

544.2117 544.2104 >10000 207.9 494 3.7 >10000 279

15.9 9.4 280

518.1597 518.1578 >10000 170.1 2034 1.5 >10000 281

529.0329 529.0353 >10000 70.4 276.1 1.3 >10000 282

525.0824 525.0827 >10000 43.3 704.3 2.6 >10000 283

468.1263 468.1257 186.2 29.3 284

543.0485 543.0500 >10000 10.1 18.5 1.1 >10000 285

539.0980 539.0978 >10000 16.7 23.6 1.8 >10000 286

482.1420 482.1421 >10000 74.9 1134.5 4.0 >10000 287

553.1137 553.1137 >10000 3.6 16.4 0.8 >10000 288

509.0875 509.0880 >10000 2.3 10.6 0.8 >10000 289

527.1852 527.1838 >10000 2720.2 >10000 10.1 >10000 290

>10000 (>10000) 590.2 (1009.04) >10000 (>10000) 1.1 (0.547) >10000(>10000) 291

100 8.0 292

970 14.4 163.5 2.4 >10000 293

6147 2.3 447.9 2.6 >10000 294

4623 100.0 447.9 4.3 >10000 295

>10000 15.6 172.1 2.6 >10000 296

1335.9 564.8 297

454.0944 454.0986 6812 8.1 64.6 0.5 6562 298

561.2634 561.2641 11.9 18.1 299

498.1586 498.1588 3.2 0.1 300

524.1743 524.1729 12.5 6.7 301

492.1692 492.1687 3655.3 0.2 9.1 <0.1 319.9 302

496.1197 496.1192 2728.9 0.2 2.9 0.1 94.9 303

576.2016 576.2198 50.0 9.9 304

538.1648 538.1629 138.6 0.2 305

569.1474 569.1444 175.9 3.9 306

>10000 92.9 185.2 1.7 >10000 307

8135 135 139.5 4.5 >10000 308

519.1801 519.1780 >10000 175.8 1601.1 3.7 >10000 309

519.1801 519.1772 >10000 135.3 1557.8 1.8 >10000 310

>10000 32.0 1980.5 3.0 >10000 311

543.2165 543.2165 25.6 2.6 312

529.1645 529.1635 9.1 0.2 313

511.1539 511.1535 18.1 <0.1 314

7.8 2.5 315

12.8 12.7 316

558.2274 558.2274 2678 2842 692.0 13.6 >10000 317

501.1695 501.1693 >10000 120.4 244.3 3.1 >10000 318

615 97.3 319

>10000 5.8 258 1.0 4225 320

5864 6110 321

>10000 1701 625.6 3.7 >10000 322

601.2220 601.2226 354 233 323

358.8 108 324

468.1151 468.1148 2990 4.2 500 0.5 8002 325

538.1899 538.1918 >10000 11.0 4042 0.5 >10000 326

462.1586 462.1582 >10000 7.4 263 0.3 8316 327

518.2212 518.2203 >10000 50.7 5284 0.9 >10000 328

542.1849 542.1866 61.3 <0.1 329

103.1 8.6 330

539.0980 539.0985 >10000 261.7 216 16.0 592 331

506.1961 506.1954 386 261.4 332

2459 3.6 132.4 2.6 >10000 333

557.0552 557.0562 >10000 656.3 3240 1.8 >10000 334

489.2059 489.2073 >10000 16.4 866 5.1 2876 335

607.2325 607.233 >10000 2.3 172.3 6.5 >10000 336

669.2482 669.2463 300.6 19.8 337

563.2427 563.2414 41.9 12.2 338

549.2271 549.2242 20.6 137.7 339

478.1648 478.1631 1205.8 932.9 340

534.2162 534.2161 >10000 253.0 5590 1.9 >10000 341

495.0718 495.0689 >10000 16.8 1122 0.5 6400 342

512.1743 512.1769 >10000 41.2 2165 2.0 >10000 343

7702.4 2.4 344

575.2791 575.2819 12.7 4.6 345

520.2005 520.1988 271.1 14.3 346

532.1754 532.171 >10000 2.6 2010 0.9 >10000 347

10.3 1.8 348

>10000 61.8 >10000 4.4 >10000 349

505.3 39.0 350

479.1488 479.1484 3283 2.6 271 0.5 2670 351

522.1798 522.1791 >10000 34.1 2225 1.0 >10000 352

498.1586 498.1576 >10000 33.6 3601 2.0 6238 353

524.1743 524.1703 >10000 25.1 1152 1.8 >10000 354

528.1692 528.1658 355

504.2056 504.2017 >10000 17.4 1072 1.1 3622 356

524.1743 524.1731 >10000 33.1 1650 0.8 >10000 357

506.1961 506.1964 >10000 10.2 952 1.7 >10000 358

492.1804 492.1813 768.4 14.6 359

488.1855 488.1862 >10000 2.3 1183 1.0 7956 360

503.2216 503.2226 >10000 9.7 547 6.4 962 361

506.1961 516.1965 6000 500 >10000 0.5 >10000 362

523.1750 523.1763 347 3.7 363

493.1645 493.1660 430 7 364

535.2114 535.2105 >10000 250 >10000 1.8 >10000 365

539.1852 539.1846 21 0.6 366

513.1695 513.1699 347 0.3 367

488.1491 488.1496 235 4.5 368

521.1594 521.1594 >10000 150 9000 0.8 >10000 369

508.1390 508.1390 155 1.5 370

505.2008 505.1990 900 37 371

491.1852 491.1894 >10000 1100 9600 2.4 >10000 372

479.1488 479.1491 210 6 373

491.1852 491.1843 >10000 940 3945 7 >10000 374

519.2165 519.2148 800 8 375

513.1695 513.1695 425 17 376

529.1645 529.1625 >10000 360 >10000 0.8 >10000 377

559.1750 559.1761 1271 5.9 378

545.1594 545.1596 655 2.7 379

545.1594 545.1585 258 10 380

543.1801 543.1835 450 0.2 381

498.1102 498.1090 193 1.4 382

464.1491 464.1475 59 1.7 383

464.1491 464.1487 351 7.5 384

532.0712 532.0709 >10000 176 2628 0.8 >10000 385

464.1491 464.1490 4341 253 >10000 3.3 >10000 386

468.1441 468.1459 >10000 131 35.3 1.2 9725 387

488.1491 488.1508 83 2.2 388

529.1645 529.1640 185 2 389

514.1648 514.1623 47 0.5 390

514.1648 514.1641 >10000 907 >10000 2.7 >10000 391

466.1648 466.1647 900 7 392

521.1958 521.1947 >10000 >10000 >10000 40 >10000 393

479.1488 479.1497 50 45 394

506.1961 506.1961 3200 1900 395

506.1961 506.1947 6000 305 396

507.1801 507.1807 4 4 397

520.2117 520.2093 3 14 398

433 433 730 22 399

469.2008 469.1988 650 8 400

455.1852 455.1843 326 9 401

551.1287 551.1264 700 25 402

471.2165 471.2144 454 30 403

457.2008 457.1997 >10000 454 >10000 5.2 >10000 404

505.2008 505.1992 254 15 405

521.5321 521.2323 >10000 2352 >10000 1.9 >10000 406

545.2434 545.2441 >10000 2200 >10000 4 >10000 407

561.0324 561.0366 285 25 408

527.0713 527.0694 >10000 90 49 2.5 6813 409

547.0167 547.0196 >10000 23 160 1 5644 410

479.0947 479.0978 4700 12 202 1.1 515 411

463.1175 463.1204 >10000 1517 >10000 587 >10000 412

475.1903 475.0916 313 41 413

489.2059 489.2068 61 8 414

503.2216 503.2215 37 14 415

517.2372 517.2377 >10000 51 1784 15 >10000 416

533.2321 533.2314 17 8.6 417

463.1539 463.1546 315 2.6 418

>10000 1500 >10000 64 >10000 419

120 4 420

>10000 67 >10000 4 >10000 421

649 256 422

7200 1484 423

9000 1585 424

485 192 425

>10000 3308 426

>10000 5151 427

251 114 428

20 1.4 429

6.5 >10000 0.5 >10000 430

2700 195 431

115 4 432

7 1.5 433

220 7 434

1.1 0.6 435

>10000 >10000 500 436

>10000 1500 100 437

>10000 >10000 >10000 90 >10000 438

>10000 505 3800 11 >10000 439

>10000 2000 6000 25 >10000 440

>10000 4 140 1 2500 441

9000 13 110 2 2290 442

>10000 6.2 5.4 1.8 997 443

>10000 25 375 3.5 2429 444

8.9 7.6 445

3325 2.2 44 0.5 546 446

76 6.6 447

>10000 8.9 12.2 2 1360 448

3080 9 116 2.7 832 449

1929 3.7 41 7 58 450

>10000 6.6 44 0.9 4937 451

4.7 9 452

2.2 14.8 453

>10000 13 800 3 5000 454

>10000 165 27 455

900 690 456

425 350 457

>10000 >10000 >10000 458

>10000 3500 1400 459

>10000 700 670 460

>10000 145 700 25 >10000 461

>10000 2200 590 462

>10000 11 18 7 6500 463

484.1794 484.1776 17 7 464

498.195 498.1925 46 1.4 465

450.1586 450.1577 >10000 4 180 0.3 1800 466

480.1692 480.1732 >10000 110 45 15 >10000 467

>10000 940 450 120 >10000 468

>10000 2500 1500 469

>10000 145 60 470

>10000 7 3 471

>10000 270 120 472

>10000 3 40 6 400 473

>10000 5 45 5 600 474

>10000 12 3 475

>10000 30 120 2 3600 476

>10000 2500 >10000 230 >10000 477

1300 1.5 2 478

>10000 1 34 5 1450 479

2700 4 14 3 2000 480

4200 18 60 11 1400 481

1.3 2 482

3300 40 483

2000 29 484

640 12 485

4000 64 486

>10000 106 255 4.6 >10000 487

>10000 3.1 169 0.5 1570 488

505.2008 505.1991 489

512.1743 512.1766 >10000 58.2 >10000 0.4 >10000 490

491.1852 491.1856 >10000 18.2 928 0.2 5630 491

478.1536 478.1540 7310 6.8 94.2 0.8 981 492

448.1430 448.1428 3550 3.5 67.3 0.7 574 493

471.1695 471.1695 4770 15.9 752 0.9 3230 494

464.1392 464.1379 1520 <0.1 13.6 <0.1 197 495

434.1273 434.1277 815 1.9 25.8 1.7 505 496

578.2172 578.2164 242 8.4 497

472.1754 472.1769 1450 23.5 498

522.191 522.1915 160 14.8 499

508.1754 508.1753 56.2 7.0 500

494.1597 494.1596 2390 1.9 63.2 8.5 2960 501

518.1597 518.158 >10000 184 7710 1.4 >10000 502

513.0557 513.0574 >10000 22.7 160 1.0 5640 503

475.1903 475.1907 504

514.1700 514.1735 (>10000) (434) (2310) (4.65) (>10000) 505

414.1581 414.1586 (850) (2.56) (10.2) (0.81) (962) 506

428.1738 428.1751 (1465) (1.92) (11.4) (0.23) (681) 507

400.1767 400.1788 (3590) (0.84) (0.44) (0.19) (444) 508

554.2319 554.2347 (4850) (22.8) (160) (0.141) (2790) 509

554.2319 554.2308 (>10000) (89.26) (50.85) (0.297) (4158.92) 510

(>10000) (7.85) (39.82) (0.25) (2183.66) 511

571.2273 571.2255 (>10000) (525.78) (38.53) (1.36) (>10000) 512

571.2273 571.2281 (>10000) (757.99) (25.71) (1.07) (>10000) 513

589.2178 589.2193 (>10000) (879.71) (254.58) (0.98) (9274.4) 514

578.2319 578.2305 (>10000) (292.63) (223.53) (0.28) (4082.05) 515

>10000 89.76 154.32 24.23 >10000 516

>10000 41.94 119.72 9.55 9434.24 517

>10000 34.66 137.63 6.19 >10000 518

>10000 26.35 115.39 169.48 967.13 519

>10000 170.25 421.64 2.18 >10000 520

>10000 54.24 36.38 0.62 4296.13 521

62.0 5.8 522

(>10000) 12.9 (32.1) (135) 0.3 (6290) 523

515.1647 515.1690 8069 (3213) 161.6 (196.7) 1647.2 (1253) 0.3(0.234) >10000 (>10000) 524

497.1741 497.1763 >10000 38.3 (51.8) 1841.5 (739.5) 0.2 (0.244) >10000(>10000) 525

520.1576 520.1581 7.5 1.5 526

557.1871 557.1863 557.1843 (>10000) (1680) (2070) (3.96) (>10000) 527

(5100) (21.3) (30.4) (.044) (1360) 528

(>10000) (83.5) (238) (2.57) (5700) 529

529.2003 529.1982 (>10000) (3550) (1870) (20.2) (>10000) 530

512.1738 512.1774 (>10000) (699) (220) (7.33) (>10000) 531

498.1581 498.1614 (>10000) (337) (774) (2.72) (>10000) 532

498.1581 498.1610 (>10000) (739) (1320) (1.02) (>10000) 533

(>10000) (29.3) (141) (0.226) (6680) 534

(>10000) (25.4) (324) (0.493) (6810) 535

(>10000) (23.2) (128) (0.261) (3870) 536

(>10000) (744) (3400) (3.4) (>10000) 537

535.1138 535.1160 (>10000) (985) (900) (0.657) (>10000) 538

540.2163 540.2142 (>10000) (24.6) (117) (0.184) (1700) 539

540.2163 540.2160 (9130) (38.6) (85.5) (0.21) (1180) 540

557.2116 557.2132 (>10000) (270) (689) (0.58) (>10000) 541

561.1295 561.1266 (>10000) (302.15) (269.03) (0.24) (>10000) 542

544.1571 544.1566 (>10000) (234.13) (921.73) (0.86) (>10000) 543

564.2163 564.2192 (>10000) (124.15) (207.41) (0.23) (3094.73) 544

557.2116 577.2087 (>10000) (302.23) (787.01) (0.898) (>10000) 545

557.2116 557.2101 (>10000) (309.81) (922.55) (1.11) (>10000) 546

575.2022 557.5023 (>10000) (426.17) (1269.5) (1.06) (>10000) 547

573.1821 573.1848 (>10000) (727.08) (1863.44) (2.28) (>10000) 548

540.2163 540.2193 (>10000) (1.58) (278.57) (0.38) (7415.08) 549

575.2022 575.2042 (>10000) (503.95) (1770.79) (1.87) (>10000) 550

(>10000) (5.49) (7.51) (0.52) (2180) 551

(>10000) (5.07) (48.2) (0.62) (2055) 552

(>10000) (4.94) (2.22) (1.78) (2440) 553

546.1905 546.1896 (>10000) (7.797) (71.205) (0.259) (2257.112) 554

(>10000) (61.27) (442.07) (14.50) (>10000) 555

(>10000) (3.383) (50.012) (0.261) (688.63) 556

(8972.84) (68.058) (211.92) (53.22) (3496.68) 557

(>10000) (6.46) (33.57) (3.68) (52.23) 558

562.1676 562.1714 (>10000) (352.06) (1357.7) (2.163) (>10000) 559

(>10000) (11.65) (57.56) (1.51) (845.5) 560

(>10000) (10.26) (7.17) (0.616) (549.16) 561

579.1400 579.1389 (>10000) (336.04) (467.44) (0.31) (>10000) 562

488.1486 488.1476 (2738.33) (241.03) (785.83) (2.97) (9265.67) 563

496.1425 496.1453 (>10000) 73.5 (70.11) (132.06) 1.1 (0.70) (4400.5) 564

455.1343 455.1345 144.9 19.4 565

545.1813 545.1825 14.0 1.6 566

467.1595 467.1643 65.7 18.8 567

549.0931 549.0955 660.5 21.9 568

489.1438 489.1435 21.0 1.5 569

506.1050 506.1028 1405 171.8 570

(3061.49) 4.8 (10.09) (6.15) 0.2 (0.142) (1357.46) 571

11.9 1.6 572

37.3 4.7 573

556.1223 556.1214 1707.7 75.1 574

(>10000) 29.4 (112.25) (83.02) 0.7 (1.32) (5386.06) 575

8.4 2.0 576

506.1050 506.1069 >10000 232.7 397.0 0.3 >10000 577

48.2 1.2 578

489.1438 489.1428 (>10000) 20.5 (72.1) (578) 2.9 (1.72) (>10000) 579

595.1743 595.1767 >10000 37.8 136.0 0.4 >10000 580

555.1430 555.1454 >10000 136.0 417.2 0.6 >10000 581

536.1156 536.1173 2534.3 29.8 582

460.1571 460.1573 55.7 25.3 583

15.7 1.6 584

(2760) 72.9 (20.8) (12.6) 3.6 (0.944) (6630) 585

85.4 4.0 586

10.1 0.6 587

538.1164 538.1191 >10000 (>10000) 81.7 (124.9) 1372.9 (8180) 0.1(1.424) >10000 (4154) 588

492.1804 492.1773 94.9 15.0 589

506.1050 506.1054 9.9 0.4 590

857.7 48.0 591

536.1348 536.1372 >10000 (>10000) 3.5 (4.4) 12.0 (4.22) 0.3(0.19) >10000 (8742.7) 592

502.1648 502.1639 336.4 38.7 593

504.1263 504.1254 6.5 15.6 594

140.1 3.8 595

502.1353 502.1359 >10000 (>10000) 482.5 (586.2) 1733 (2056.6) 1.0(7.245) >10000 (>10000) 596

519.1260 519.1265 >10000 (>10000) 10.3 (11.2) 194.5 (307.7) 2.7 (0.398)2491 (1160) 597

521.0875 521.0910 471.1 12.1 598

522.0827 522.0932 (>10000) (599.35) (705.33) (0.27) (>10000) 599

488.1491 488.1491 >10000 (>10000) <0.1 (0.38) 11.6 (11.34) 0.1 (0.24)57.01 600

448.1542 448.1542 205.7 214.4 601

469.1103 469.1093 4916 1.9 42.6 1.3 2062 602

493,1639 493,1608 13.7 3.6 603

515.1158 515.1145 34.0 2.4 604

36.6 3.3 605

44.0 3.8 606

489.1332 489.1326 >10000 (>10000) 5.0 (11.574) 234.0 (105.89) 0.4(0.432) 2566 (2053.20) 607

520.1264 520.1297 >10000 45.2 2298 0.1 >10000 608

586.1181 586.1160 >10000 (>10000) 342.1 (723.95) 1794 (1368.3) 6.6(9.34) >10000 (>10000) 609

>10000 579.9 6887 7.7 >10000 610

488.3 4.1 611

733.2 13.6 612

504.2414 504.2413 1232.2 16.1 613

34.3 6.6 614

562.1504 562.1516 >10000 1.8 8.5 0.7 9440 615

566.1443 566.1453 >10000 1.1 3.6 0.4 6696 616

493,1645 493.1617 1584 5.3 54.8 2.0 1969 617

469.1103 469.1086 2074 1112 0.8 413 0.6 4133 618

822.1 27.5 619

66.2 1.5 620

16.2 4.1 621

488.1491 488.1489 367.6 17.8 622

505.1103 505.1120 >10000 (>10000) 273.1 (450.85) 1756 (2077.1) 1.5(2.68) >10000 (>10000) 623

546.1733 546.1728 >10000 5.2 3.1 1.2 5520 624

521.1746 521.1753 >10000 (>10000) 214.4 (623) 1029 (443) 0.3(0.9) >10000 (7580) 625

564.1668 564.1643 (>10000) 3499.5 (6860) (4600) 33.6 (43.6) (>10000) 626

558.191 558.1925 >10000 (>10000) 142.8 (645) 885 (1100) 0.4 (7.5) >10000(>10000) 627

554.1849 554.1884 (>10000) 2072.7 (3950) (3150) 14.9 (40.9) (>10000) 628

540.1692 540.1712 >10000 (>10000) 1701.3 (2750) 1754 (1930) 3.3(19.8) >10000 (>10000) 629

546.1950 546.1965 (>10000) 536.8 (1020) (1300) 78.6 (89.1) (>10000) 630

532.1605 532.1598 >10000 (>10000) 1166.6 (2070) 5990 (2280) 0.4(6.02) >10000 (>10000) 631

552.1515 552.1520 (>10000) 2143.2 (4960) (5810) 117.7 (57.6) (>10000)632

502.1358 502.1387 >10000 (>10000) 91.0 (279) 411 (716) 1.6 (6.54) >10000(>10000) 633

552.1515 552.1510 (>10000) 2828.1 (4580) (6780) 117.0 (92.4) (>10000)634

536.1743 536.1730 (>10000) 486.4 (983) (1300) 16.3 (19.4) (>10000) 635

522.1950 522.1973 (>10000) 2309.5 (4680) (4830) 20.0 (26.2) (>10000) 636

512.1743 512.1755 (>10000) 195.0 (527) (763) 3.2 (3.21) (>10000) 637

486.1586 486.1576 >10000 (>10000) 137.6 (498) 830 (881) 1.8(4.63) >10000 (>10000) 638

546.1950 546.1950 (>10000) 4400.9 (8120) (8770) 400.4 (68.1) (>10000)639

516.1515 516.1501 (>10000) 247.1 (505) (688) 4.3 (12.5) (>10000) 640

476.2101 476.2114 324.5 10.4 641

134.7 5.0 642

528.1799 528.1771 2889.0 36.9 643

4-[(4-{3-[(1-adamantylcarbonyl)amino]propoxy}phenyl)sulfonyl]-1-cyclopropyl-N-hydroxypiperidine-4-carboxamide hydrochloride 560.2794560.2793 1134.1 11.4 644

4-[(4-{3-[(1-adamantylcarbonyl)(methyl)amino]propoxy}phenyl)sulfonyl]-1-cyclopropyl-N-hydroxypiperidine-4-carboxamide hydrochloride 574.2951574.2943 2633.4 20.9 645

4-[(4-{3-[(2-adamantylamino)sulfonyl]propoxy}phenyl)sulfonyl]-N-hydroxytetrahydro-2H-pyran-4-carboximide 557 557 9283 22.9 17264.3 >10000 646

(>10000) (288.84) (76.21) (0.16) (4296.95)

The above detailed description of preferred embodiments is intended onlyto acquaint others skilled in the art with the invention, itsprinciples, and its practical application so that others skilled in theart may adapt and apply the invention in its numerous forms, as they maybe best suited to the requirements of a particular use. This invention,therefore, is not limited to the above embodiments, and may be variouslymodified.

1. A compound or salt thereof, wherein: the compound corresponds instructure to Formula 122-1:

A¹ is selected from the group consisting of —H, alkylcarbonyl,alkoxycarbonyl, carbocyclylcarbonyl, carbocyclyalkylcarbonyl,heterocyclylcarbonyl, heterocyclylalkylcarbonyl, carbocyclyloxycarbonyl,carbocyclylalkoxycarbonyl, aminoalkylcarbonyl, alkyl(thiocarbonyl),alkoxy(thiocarbonyl), carbocyclyl(thiocarbonyl),carbocyclylalkyl(thiocarbonyl), heterocyclyl(thiocarbonyl),heterocyclylalkyl(thiocarbonyl), carbocyclyloxy(thiocarbonyl),carbocyclylalkoxy(thiocarbonyl), and aminoalkyl(thiocarbonyl), whereinany member of such group optionally is substituted; and A² and A³,together with the carbon atom to which they are both attached, form anoptionally-substituted heterocyclyl containing from 5 to 8 ring members;and E¹ is selected from the group consisting of —O—, —S(O)₂—, —S(O)—,—N(R¹)—, —C(O)—N(R¹)—, —N(R¹)—C(O)—, and —C(R¹)(R²)—; and E² is selectedfrom the group consisting of alkyl, cycloalkyl, alkylcycloalkyl,cycloalkylalkyl, and alkylcycloalkylalkyl, wherein any member of suchgroup optionally is substituted; and E² forms a link of at least 2carbon atoms between E¹ and E³; and E³ is carbocyclyl wherein thecarbocyclyl has 5 or 6 ring members and optionally is substituted; andE⁴ is selected from the group consisting of a bond, alkyl, alkenyl, —O—,and, —N(R³)—, wherein the alkyl or alkenyl optionally is substituted;and E⁵ is selected from the group consisting of carbocyclyl andheterocyclyl, wherein the carbocyclyl or heterocyclyl optionally issubstituted; and R¹ and R² are independently selected from the groupconsisting of —H and alkyl, wherein the alkyl optionally is substituted;and R³ is selected from the group consisting of —H and alkyl, whereinthe alkyl optionally is substituted; and neither R¹ nor R² forms a ringstructure with E², E³, E⁴, or E⁵.
 2. A compound or salt thereofaccording to claim 1, wherein: A¹ is selected from the group consistingof —H, C₁-C₈-alkylcarbonyl, C₁-C₈-alkoxycarbonyl, carbocyclylcarbonyl,carbocyclyl₁-C₈-alkylcarbonyl, heterocyclylcarbonyl,heterocyclyl-C₁-C₈-alkylcarbonyl, carbocyclyloxycarbonyl,carbocyclyl-C₁-C₈-alkoxycarbonyl, N(R⁴)(R⁵)—C₁-C₈-alkylcarbonyl,C₁-C₈-alkyl(thiocarbonyl), C₁-C₈-alkoxy(thiocarbonyl),carbocyclyl(thiocarbonyl), carbocyclyl-C₁-C₈-alkyl(thiocarbonyl),hetermcyclyl(thiocarbonyl), heterocyclyl-C₁-C₈alkyl(thiocarbonyl),carbocyclyloxy(thiocarbonyl), carbocyclyl-C₁-C₈-alkoxy(thiocarbonyl),and N(R⁴)(R⁵)—C₁-C₈-alkyl(thiocarbonyl); and E² is selected from thegroup consisting of C₂-C₂₀-alkyl, cycloalkyl, C₁-C₁₀-alkylcycloalkyl,cycloalkyl-C₁-C₁₀-alkyl, C₁-C₁₀-alkylcycloalkyl-C₁-C₁₀-alkyl, whereinany member of such group optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁-C₆ alkyl, and halo-C₁-C₆-alkyl; and E³ is carbocyclyl,wherein the carbocyclyl: has 5 or 6 ring members, and optionally issubstituted with one or more substituents independently selected fromthe group consisting of halogen, —OH, keto, C₁-C₈-alkyl, C₁-C₈-alkoxy,C₁-C₈-alkoxy-C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl,heterocyclyl, and heterocyclyl-C₁-C₈-alkyl, wherein: any suchsubstituent optionally is substituted with one or more substituentsindependently selected from the group consisting of halogen, —OH,C₁-C₈-alkyl, C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl, C₁-C₈-alkylthio,halo-C₁-C₈-alkyl, halo-C₁-C₈-alkoxy, halo-C₁-C₈-alkylthio, andhalogen-substituted C₁-C₈-alkoxy-C₁-C₈-alkyl; and E⁴ is selected fromthe group consisting of a bond, —O—, —N(R³)—, C₁-C₂₀-alkyl, andC₂-C₂₀-alkenyl, wherein the C₁-C₂₀-alkyl or C₂-C₂₀-alkenyl optionally issubstituted with one or more substituents independently selected fromthe group consisting of: halogen, and carbocyclyl optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, —OH, —NO₂, —CN, C₁-C₈-alkyl, C₁-C₈-alkoxy,C₁-C₈-alkoxy-C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl,halo-C₁--C₈-alkyl, halo-C₁-C₈-alkoxy, halocarbocyclyl,halogen-substituted carbocyclyl-C₁-C₈-alkyl, and halogen-substitutedC₁-C₈-alkoxy-C₁-C₈alkyl; and E³ is selected from the group consisting ofcarbocyclyl and heterocyclyl, wherein the carbocyclyl or heterocyclyloptionally is substituted with one or more substituents independentlyselected from the group consisting of halogen, —OH, —NO₂, —CN, keto,C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₁-C₈-alkoxy,C₁-C₈-alkoxy-C₁-C₈-alkyl, —N(R⁶)(R⁷), —C(O)(R⁸), —S—R⁶, —S(O)₂—R⁶,carbocyclyl, carbocyclyl-C₁-C₈-alkyl, halo-C₁-C₈-alkyl,halo-C₁-C₈-alkoxy, halogen-substituted C₁-C₈-alkoxy-C₁-C₈-alkyl,halocarbocyclyl, and halogen-substituted carbocyclyl-C₁-C₈-alkyl; and R¹and R² are independently selected from the group consisting of —H,C₁-C₈-alkyl, and halo-C₁-C₈-alkyl; and R³ is selected from the groupconsisting of —H, C₁-C₈-alkyl, and halo-C₁-C₈-alkyl; and R⁴ and R⁵ areindependently selected from the group consisting of —H, C₁-C₈-alkyl,C₁-C₈-alkoxycarbonyl, C₁-C₈-alkylcarbonyl, carbocyclyl-C₁-C₈-alkyl, andcarbocyclyl-C₁-C₈-alkoxycarbonyl; and R⁶ and R⁷ are independentlyselected from the group consisting of —H, C₁-C₈-alkyl, carbocyclyl,carbocyclyl-C₁-C₈-alkyl, heterocyclyl, heterocyclyl-C₁-C₈-alkyl,halo-C₁-C₈-alkyl, halocarbocyclyl, halogen-substitutedcarbocyclyl-C₁-C₈-alkyl, haloheterocyclyl, and halogen-substitutedheterocyclyl-C₁-C₈-alkyl; and R⁸ is selected from the group consistingof —H, C₁-C₈-alkyl, —O—R⁹, —N(R⁹)(R¹⁰), carbocyclyl-C₁-C₈-alkyl,heterocyclyl-C₁-C₈-alkyl, halo-C₁-C₈-alkyl, halogen-substitutedcarbocyclyl-C₁-C₈-alkyl, and halogen-substitutedheterocyclyl-C₁-C₈-alkyl; and R⁹ and R¹⁰ are independently selected fromthe group consisting of —H, C₁-C₈-alkyl, carbocyclyl,carbocyclyl-C₁-C₈-alkyl, heterocyclyl, heterocyclyl-C₁-C₈-alkyl,halo-C₁-C₈-alkyl, halocarbocyclyl, halogen-substitutedcarbocyclyl-C₁-C₈-alkyl, haloheterocyclyl, and halogen-substitutedheterocyclyl-C₁-C₈-alkyl.
 3. A compound or salt thereof according toclaim 2, wherein A¹ is —H.
 4. A compound or salt thereof according toclaim 3, wherein: E² is C₂-C₆-alkyl optionally substituted with one ormore halogen; an E³ is carbocyclyl, wherein the carbocyclyl: has 5 or 6ring members, and optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, keto, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,carbocyclyl, carbocyclyl-C₁-C₆-alkyl, heterocyclyl, andheterocyclyl-C₁-C₆-alkyl, wherein: any such substituent optionally issubstituted with one or more substituents independently selected fromthe group consisting of halogen, —OH, C₁-C₆-alkyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio, halo-C₁-C₆-alkyl,halo-C₁-C₆-alkoxy, halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl, andhalo-C₁-C₆-alkylthio; and E⁴ is selected from the group consisting of abond, —O—, —N(R³)—, C₁-C₃-alkyl, and C₂-C₃-alkenyl, wherein theC₁-C₃-alkyl or C₂-C₃-alkenyl optionally is substituted with one or moresubstituents independently selected from the group consisting of:halogen, and carbocyclyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO₂, —CN, C₁-C₆-alkyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, carbocyclyl, carbocyclyl-C₁-C₆-alkyl,halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, halogen-substitutedC₁-C₆-alkoxy-C₁-C₆-alkyl, halocarbocyclyl, and halogen-substitutedcarbocyclyl-C₆-alkyl; and E⁵ is selected from the group consisting ofcarbocyclyl and heterocyclyl, wherein the carbocyclyl or heterocyclyloptionally is substituted with one or more substituents independentlyselected from the group consisting of halogen, —OH, —NO₂, —CN, keto,C₁-C₆-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R⁶)(R⁷), —C(O)(R⁸), —S—R⁶, —S(O)₂—R⁶,carbocyclyl, carbocyclyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl,halo-C₁-C₆-alkoxy, halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl,halocarbocyclyl, and halogen-substituted carbocyclyl-C₁-C₆-alkyl; and R¹and R² are independently selected from the group consisting of —H,C₁-C₆-alkyl, and halo-C₁-C₆-alkyl; and R¹ is selected from the groupconsisting of —H, C₁-C₆-alkyl, and halo-C₁-C₆-alkyl; and R⁶ and R⁷ areindependently selected from the group consisting of —H, C₁-C₆-alkyl,carbocyclyl, carbocyclyl-C₁-C6-alkyl, heterocyclyl, andheterocyclyl-C₁-C₆-alkyl, wherein any member of such group optionally issubstituted with one or more halogen; and R⁸ is selected from the groupconsisting of —H, C₁-C₆-alkyl, —O—R⁹, —N(R⁹)(R¹⁰),carbocyclyl-C₁-C₆-alkyl, heterocyclyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl,halogen-substituted carbocyclyl-C₁-C₆-alkyl, and halogen-substitutedheterocyclyl-C₁-C₆-alkyl; and R⁹ and R¹⁰ are independently selected fromthe group consisting of —H, C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, heterocyclyl, heterocyclyl-C₁-C₆-alkyl,halo-C₁-C₆-alkyl, halocarbocyclyl, halogen-substitutedcarbocyclyl-C₁-C₆-alkyl, haloheterocyclyl, and halogen-substitutedheterocyclyls-C₁-C₆-alkyl.
 5. A compound or salt thereof according toclaim 4, wherein A² and A³, together with the carbon atom to which theyboth attached, form an optionally-substituted heterocyclyl containingeither 5 or 6 ring members.
 6. A compound or salt thereof according toclaim 5, wherein: the compound corresponds in structure to a formulaselected from the group consisting of:

A⁴ is selected from the group consisting of —H, alkyl, alkylcarbonyl,alkylcarbonylalkyl, alkylcarbonylalkylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, alkylcarbonylalkylcarbonyl, alkylsulfonyl,alkylaminocarbonyl, alkenyl, alkynyl alkoxyalkyl, alkylthioalkyl,alkylsulfonylalkyl, alkylsufoxidoalkyl, alkylthioalkenyl,alkylsulfoxidoalkenyl, alkylsulfonylalkyl, carbocyclyl,carbocyclylalkyl, carbocyclylalkoxyalkyl, carbocyclylcarbonyl,carbocyclylsulfonyl, carbocyclyliminocarbonyl, carbocyclyloxycarbonyl,carbocyclylthioalkyl, carbocyclylsulfoxidoalkyl,carbocyclylsulfonylalkyl, carbocyclylthioalkenyl,carbocyclylsulfoxidoalkenyl, carbocyclylsulfonylalkenyl, heterocyclyl,heterocyclylalkyl, heterocyclylalkoxyalkyl, heterocyclylcarbonyl,heterocyclylthioalkyl, heterocyclylsulfoxidoalkyl,heterocyclylsulfoxidoalkyl, heterocyclylthioalkyl,heterocyclylsulfoxidoalkenyl, heterocyclylsulfonylalkenyl,heterocyclylsulfonyl, heterocyclyliminocarbonyl,heterocyclylalkylcarbonyl, heterocyclylcarbonylalkylcarbonyl,heterocyclylsulfonyl, heterocyclylcarbonylalkyl, aminoalkylcarbonyl,aminocarbonyl, aminocarbonylalkylcarbonyl, aminosulfonyl,aminosulfonylalkyl, aminoalkyl, aminocarbonylalkyl, andaminoalkylsulfonyl, wherein: any member of such group optionally issubstituted.
 7. A compound or salt thereof according to claim 6,wherein: A⁴ is selected from the group consisting of —H, C₁-C₈-alkyl,C₁-C₈-alkylcarbonyl, C₁-C₈-alkylcarbonyl-C₁-C₈-alkyl,C₁-C₈-alkylcarbonyl-C₁-C₈-alkylcarbonyl, C₁-C₈-alkoxycarbonyl,C₁-C₈-alkoxycarbonyl-C₁-C₈-alkyl,C₁-C₈-alkoxycarbonyl-C₁-C₈-alkylcarbonyl, C₁-C₈-alkylsulfonyl,C₁-C₈-alkylaminocarbonyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl,C₁-C₈-alkoxy-C₁-C₈-alkyl, C₁-C₈-alkylthio-C₁-C₈-alkyl,C₁-C₈-alkylthio-C₂-C₈-alkenyl, C₁-C₈-alkylsulfoxido-C₁-C₈-alkyl,C₁-C₈-alkylsulfoxido-C₂-C₈-alkenyl, C₁-C₈-alkylsulfonyl-C₁-C₈-alkyl,C₁-C₈-alkylsulfonyl-C₂-C₈-alkenyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl,carbocyclyl-C₁-C₈-alkoxy-C₁-C₈-alkyl, carbocyclylcarbonyl,carbocyclylsulfonyl, carbocyclyliminocarbonyl, carbocyclyloxycarbonyl,carbocyclylthio-C₁-C₈-alkyl, carbocyclylthio-C₂-C₈-alkenyl,carbocyclylsulfoxido-C₁-C₈-alkyl, carbocyclylsulfoxido-C₂-C₈-alkenyl,carbocyclylsulfonyl-C₁-C₈-alkyl, carbocyclylsulfonyl-C₂-C₈-alkenyl,heterocyclyl, heterocyclyl-C₁-C₈-alkyl,heterocyclyl-C₁-C₈-alkoxy-C₁-C₈-alkyl, heterocyclylcarbonyl,heterocyclylthio-C₁-C₈-alkyl, heterocyclylsulfoxido-C₁-C₈-alkyl,heterocyclylsulfonyl-C₁-C₈-alkyl, heterocyclylthio-C₂-C₈-alkenyl,heterocyclylsulfoxido-C₂-C₈-alkenyl, heterocyclylsulfonyl-C₂-C₈-alkenyl,heterocyclylsulfonyl, heterocyclyliminocarbonyl,heterocyclyl-C₁-C₈-alkylcarbonyl,heterocyclylcarbonyl-C₁-C₈-alkylcarbonyl, heterocyclylsulfonyl,heterocyclylcarbonyl-C₁-C₈-alkyl, N(R¹¹)(R¹²)—C₁-C₈-alkylcarbonyl,N(R¹¹)(R¹²)-carbonyl, N(R¹¹)(R¹²)-carbonyl-C₁-C₈-alkylcarbonyl,N(R¹¹)(R¹²)-sulfonyl, N(R¹¹)(R¹²)-sulfonyl-C₁-C₈-alkyl,N(R¹¹)(R¹²)—C₁-C₈-alkyl, N(R¹¹)(R¹²)-carbonyl-C₁-C₈-alkyl, andN(R¹¹)(R¹²)—C₁-C₈-alkylsulfonyl, wherein: any member of such groupoptionally is substituted with one or more substitutes independentlyselected from the group consisting of halogen, —OH, —CN, —-C(O)—OH, —SH,—SO₃H, and NO₂; and R¹¹ and R¹² are independently selected from thegroup consisting of —H, —OH, C₁-C₈-alkyl, C₁-C₈-alkyl-carbonyl,C₁-C₈-alkoxy-C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₈-alkynyl,C₁-C₈-alkyl-thio-C₁-C₈-alkyl, C₁-C₈-alkyl-sulfoxido-C₁-C₈-alkyl,C₁-C₈-alkyl-sulfonyl-C₁-C₈-alkyl, carbocyclyl, carbocyclyl-C₁-C₈-alkyl,carbocyclylcarbonyl, carbocyclyl-C₁-C₈-alkoxy-C₁-C₈-alkyl,carbocyclylthio-C₁-C₈-alkyl, carbocyclylsulfoxido-C₁-C₈-alkyl,carbocyclylsulfonyl-C₁-C₈-alkyl, heterocyclyl, heterocyclyl-C₁-C₈-alkyl,heterocyclyl-C₁-C₈-alkoxy-C₁-C₈-alkyl, heterocyclylcarbonyl,heterocyclylthio-C₁-C₈-alkyl, heterocyclylsulfoxido-C₁-C₈-alkyl,heterocyclylsulfonyl-C₁-C₈-alkyl, aminocarbonyl-C₁-C₈-alkyl,C₁-C₈-alkoxycarbonylamino-C₁-C₈-alkyl, and amino-C₁-C₈-alkyl, wherein:any member of such group optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —CN, —C(O)—OH, —SH, —SO₃H, and NO₂, and the nitrogen ofthe amino-C₁-C₈-alkyl optionally is substituted with 1 or 2 substituentsindependently selected from the group consisting of C₁-C₈-alkyl,C₁-C₈-alkylcarbonyl, carbocyclyl, and carbocyclyl-C₁-C₈-alkyl, and nogreater than one of R¹¹ or R¹² is —OH.
 8. A compound or salt thereofaccording to claim 7, wherein A⁴ is selected from the group consistingof —H, C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₆-alkyl, carbocyclyl,carbocyclyl-C₁-C₆-alkyl, C₁-C₆-alkylsulfonyl, C₃-C₆-alkenyl,C₃-C₆-alkynyl, wherein any member of such group optionally issubstituted with halogen.
 9. A compound or salt thereof according toclaim 8, wherein A⁴ is selected from the group consisting of —H,C₁-C₄-alkyl, C₁-C₂-alkoxy-C₁-C₃-alkyl, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkyl-C₁-C₃-alkyl, phenyl, phenyl-C₁-C₃-alkyl,C₁-C₂-alkylsulfonyl, C₃-C₄-alkenyl, C₃-C₄-alkyl, wherein any member ofsuch group optionally is substituted with halogen.
 10. A compound orsalt thereof according to claim 9, wherein A⁴ is selected from the groupconsisting of —H, ethyl, methoxyethyl, cyclopropyl, cyclopropylmethyl,benzyl, methylsulfonyl, C₃-alkenyl, and C₃-alkenyl, wherein any memberof such group optionally is substituted with halogen.
 11. A compound orsalt thereof according to claim 10, wherein A⁴ is selected from thegroup consisting of —H, ethyl, methoxyethyl, cyclopropyl,cyclopropylmethyl, and benzyl, wherein any member of such groupoptionally is substituted with halogen.
 12. A compound or salt thereofaccording to claim 7, wherein the salt comprises an acid selected fromthe group consisting of HCl and CF₃COOH.
 13. A compound or salt thereofaccording to claim 7, wherein E² is C₂-C₅-alkyl optionally substitutedwith one or more halogen.
 14. A compound or salt thereof according toclaim 13, wherein E² is —(CH₂)_(m)—, and m is from 2 to
 5. 15. Acompound or salt thereof according to claim 14, wherein E⁴ is a bond.16. A compound or salt thereof according to claim 7, wherein E³ isselected from the group consisting of cyclopentyl, cyclopentenyl,cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl,wherein: any member of such group optionally is substituted with one ormore substituents independently selected from the group consisting ofhalogen, —OH, keto, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,carbocyclyl, carbocyclyl-C₁-C₆-alkyl, heterocyclyl, andheterocyclyl-C₁-C₆-alkyl, wherein: any such substituent optionally issubstituted with one or more substituents independently selected fromthe group consisting of halogen, —OH, C₁-C₆-alkyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl, C₁-C₆-alkylthio, halo-C₁-C₆-alkyl, haloC₁-C₆-alkoxy, halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl, andhalo-C₁-C₆-alkylthio.
 17. A compound or salt thereof according to claim16, wherein E³ is phenyl optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl,carbocyclyl, carbocyclyl-C₁-C₆-alkyl, heterocyclyl, andheterocyclyl-C₁-C₆-alkyl, wherein: any such substituent optionally issubstituted with one or more substituents independently selected fromthe group insisting of halogen, —OH, C₁-C₆-alkyl, C₁-C₆-alkoxy,C₁-C₆-alkoxy-C₁-C₆-alkyl; C₁-C₆-alkylthio, halo-C₁-C₆-alkyl,halo-C₁-C₆-alkoxy, halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl, andhalo-C₁-C₆-alkylthio.
 18. A compound or salt thereof according to claim17, wherein E⁵ is selected from the group consisting of piperidinyl,piperazinyl, imidazolyl, furanyl, thienyl, pyridinyl, pyrimidyl,benzodioxolyl, benzodioxanyl, benzofuryl, and benzothienyl, wherein anymember of such group optionally is substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO₂, —CN, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R⁶)(R⁷), —C(O)(R⁸), —S—R⁶,—S(O)₂—R⁶, phenyl, phenyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl,halo-C₁-C₆-alkoxy, halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkylhalophenyl, and halogen-substituted phenyl-C₁-C₆-alkyl.
 19. A compoundor salt thereof according to claim 18, wherein the compound correspondsin structure to a formula selected from the group consisting of:


20. A compound or salt thereof according to claim 18, wherein thecompound corresponds in structure to the following formula:


21. A compound or salt thereof according to claim 18, wherein thecompound corresponds in structure to the following formula:


22. A compound or salt thereof according to claim 18, wherein thecompound corresponds in structure to the following formula:


23. A compound or sat thereof according to claim 18, wherein thecompound corresponds in structure to the following formula:


24. A compound or salt thereof according to claim 18, wherein thecompound corresponds in structure to a formula selected from the groupconsisting of:


25. A compound or salt thereof according to claim 18, wherein thecompound corresponds in structure to a formula selected from the groupconsisting of:


26. A compound or salt thereof according to claim 18, wherein thecompound corresponds in structure to a formula selected from the groupconsisting of:


27. A compound or salt thereof according to claim 18, wherein thecompound corresponds in structure to the following formula:


28. A compound or salt thereof according to claim 18, wherein thecompound corresponds in structure to the following formula:


29. A compound or salt thereof according to claim 18, wherein thecompound corresponds in structure to the following formula:


30. A compound or salt thereof according to claim 18, wherein thecompound corresponds in structure to the following formula:


31. A compound or salt thereof according to claim 18, wherein thecompound corresponds in structure to a formula selected from the groupconsisting of:


32. A compound or salt thereof according to claim 17, wherein E⁵ isselected from the group consisting of phenyl and naphthalenyl, wherein:the phenyl and naphthalenyl optionally are substituted with one or moresubstituents independently selected from the group consisting ofhalogen, —OH, —NO₂, —CN, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, —N(R⁶)(R⁷), —C(O)(R⁸), —S—R⁶,—S(O)₂—R⁶, phenyl, phenyl-C₁-C₆-alkyl, halo-C₁-C₆-alkyl,halo-C₁-C₆-alkoxy, halogen-substituted C₁-C₆-alkoxy-C₁-C₆-alkyl,halophenyl, and halogen-substituted phenyl-C₁-C₆-alkyl.
 33. A compoundor salt thereof according to claim 32, wherein the compound correspondsin structure to a formula selected from the group consisting of:


34. A compound or salt thereof according to claim 32, wherein thecompound corresponds in structure to a formula selected from the groupconsisting of:


35. A compound or salt thereof according to claim 32, wherein thecompound corresponds in structure to the following formula:


36. A compound or salt thereof according to claim 32, wherein thecompound corresponds in structure to the following formula:


37. A compound or salt thereof according to claim 32, wherein thecompound corresponds in structure to the following formula:


38. A compound or salt thereof according to claim 32, wherein thecompound corresponds in structure to the following formula:


39. A compound or salt thereof according to claim 32, wherein thecompound corresponds in structure to the following formula:


40. A compound or salt thereof according to claim 32, wherein thecompound corresponds in structure to the following formula:


41. A compound or salt thereof according to claim 32, wherein thecompound corresponds in structure to the following formula:


42. A compound or salt thereof according to claim 32, wherein thecompound corresponds in structure to the following formula:


43. A method for treating a pathological condition associated withpathological matrix metalloprotease activity in a mammal, wherein: thecondition is selected from the group consisting of arthritis, cancer, anophthalmologic condition, and cardiovascular condition; and the methodcomprises administering a compound or a pharmaceutically acceptable saltthereof in a therapeutically effective amount to the mammal; and thecompound is selected from the group of compounds recited in claim
 1. 44.A method according to claim 43, wherein the compound or salt inhibitsthe activity of one or more of MMP-2, MMP-9, and MMP-13, whileexhibiting substantially less inhibitory activity against both MMP-1 andMP-14.
 45. A method according to claim 44, wherein the compound or saltinhibits the activity of MMP-13, while exhibiting substantially lessinhibitory activity against both MMP-1 and MMP-14.
 46. A methodaccording to claim 45, wherein the pathological condition is selectedfrom the group consisting of arthritis and a cardiovascular condition.47. A method according to claim 44, wherein the compound or saltinhibits the activity of both MMP-2 and MMP-9, while exhibitingsubstantially less inhibitory activity against both MMP-1 and MP-14. 48.A method according to claim 47, wherein the pathological condition isselected from the group consisting of cancer, an ophthalmologiccondition, and a cardiovascular condition.
 49. A method for treating apathological condition in a mammal, wherein: the method comprisesadministering a compound or a pharmaceutically acceptable salt thereofin a therapeutically-effective amount to the mammal; and the compound isselected from the group of compounds recited in claim 1; and thepathological condition is selected from the group consisting of tissuedestruction, a fibrotic disease, matrix weakening, defective injuryrepair, a cardiovascular disease, a pulmonary disease, a kidney disease,a liver disease, an ophthalmologic disease, and a central nervous systemdisease.
 50. A method for treating a pathological condition in a mammal,wherein: the method comprises administering a compound or apharmaceutically acceptable salt thereof in a therapeutically-effectiveamount to the mammal; and the compound is selected from the group ofcompounds recited in claim 1; and the pathological condition is selectedfrom the group consisting of osteoarthritis, rheumatoid arthritis,septic arthritis, tumor invasion, tumor metastasis, tumor angiogenesis,a decubitis ulcer, a gastric ulcer, a corneal ulcer, periodontaldisease, liver cirrhosis, fibrotic lung disease, otosclerosis,atherosclerosis, multiple sclerosis, dilated cardiomyopathy, epidermalulceration, epidermolysis bullosa, aortic aneurysm, defective injuryrepair, an adhesion, scarring, congestive heart failure, post myocardialinfarction, coronary thrombosis, emphysema, proteinuria, Alzheimer'sdisease, bone disease, and chronic obstructive pulmonary disease.
 51. Amethod for treating a pathological condition associated withpathological TNF-α convertase activity in a mammal, wherein: thepathological condition is selected from the group consisting ofinflammation, a pulmonary disease, a cardiovascular disease, anautoimmune disease, graft rejection, a fibrotic disease, multiplesclerosis, cancer, an infectious disease, fever, psoriasis, hemorrhage,coagulation, radiation damage, acute-phase responses of shock andsepsis, anorexia, and cachexia; and the method comprises administering acompound or a pharmaceutically acceptable salt thereof in atherapeutically-effective amount to the mammal; and the compound isselected from the group of compounds recited in claim
 1. 52. A methodfor treating a pathological condition associated with pathologicalaggrecanase activity in a mammal, wherein: the condition is selectedfrom the group consisting of inflammation condition and cancer; and themethod comprises administering a compound or a pharmaceuticallyacceptable salt thereof in a therapeutically-effective amount to themammal; and the compound is selected from the group of compounds recitedin claim
 1. 53. A pharmaceutical composition comprising atherapeutically-effective amount of a compound or apharmaceutically-acceptable salt thereof, wherein the compound isselected from the group of compounds recited in claim 1.